Benzopyranopyrazolyl derivatives for the treatment of inflammation

ABSTRACT

A class of benzopyranopyrazolyl derivatives is described for use in treating inflammation and inflammation-related disorders. Compounds of particular interest are defined by Formula I ##STR1## wherein A, wherein X, m, n, p, B, R 1 , R 2 , and R 4  are as described in the specification.

This application is a 371 of PCT U.S. 95/11403 filed on Sep. 15, 1995.

FIELD OF THE INVENTION

This invention is in the field of antiinflammatory pharmaceutical agentsand specifically relates to compounds, compositions and methods fortreating inflammation and inflammation-associated disorders, such asarthritis.

BACKGROUND OF THE INVENTION

Prostaglandins play a major role in the inflammation process and theinhibition of prostaglandin production, especially production of PGG₂,PGH₂ and PGE₂, has been a common target of antiinflammatory drugdiscovery. However, common non-steroidal antiinflammatory drugs (NSAIDs)that are active in reducing the prostaglandin-induced pain and swellingassociated with the inflammation process are also active in affectingother prostaglandin-regulated processes not associated with theinflammation process. Thus, use of high doses of most common NSAIDs canproduce severe side effects, including life threatening ulcers, thatlimit their therapeutic potential. An alternative to NSAIDs is the useof corticosteroids, which have even more drastic side effects,especially when long term therapy is involved.

Previous NSAIDs have been found to prevent the production ofprostaglandins by inhibiting enzymes in the human arachidonicacid/prostaglandin pathway, including the enzyme cyclooxygenase (COX).The recent discovery of an inducible enzyme associated with inflammation(named "cyclooxygenase-2 (COX-2)" or "prostaglandin G/H synthase II")provides a viable target of inhibition which more effectively reducesinflammation and produces fewer and less drastic side effects.

The novel compounds described herein are such safe and also effectiveantiinflammatory agents. The invention compounds are found to showusefulness in vivo as antiinflammatory agents with minimal side effects.The compounds described herein preferably selectively inhibitcyclooxygenase-2 over cyclooxygenase-1.

Substituted pyrazoles having antiinflammatory activity are described incopending applications 08/160,594 and 08/160,553.

U.S. Pat. No. 3,940,418 to R. Hamilton describes tricyclic4,5-dihydrobenz g!indazole-3-carboxylic acids as antiinflammatoryagents.

U.S. Pat. No. 4,803,193 to Kanda et al, describes spiro 3-alkyl-1-aryl1!benzopyrano 4,3-c!pyrazole-4(1H),9'- 9H!fluorenes as heat sensitiverecording matertials.

V. Colota et al (J.Med.Chem., 33, 2646 (1991)) describe tricyclicheteroaramatic systems, including 1-aryl-pyrazolo 4,5-c!quinolin-4-ones,1-aryl-pyrazolo 4,5-c! 1,8!naphthyridin-4-ones and 1-aryl- 1!benzopyrano3,4-d!pyrazol-4-ones for CNS applications. F. Melani et al J.Med.Chem.,29, 291 (1986) also describe 1-phenyl-pyrazolo 4,5-c!quinolines for CNSapplications.

U.S. Pat. Nos. 4,816,467 and 5,206,258 to Doria et al describe(2-cyano-3-(1,4-dihydro)-1-phenyl- 1!benzothiopyrano4,3-c!pyrazol-3-yl)-3-oxo-propanamides as immunomodulators. G. Doria etal (Farmaco, 46, 843 (1991)) also describe the immunomodulating activityof pyrazolylpropanamides, and specifically ethyl1-(4-fluorophenyl)-1,4-dihydro- 1!benzothiopyrano4,3-c!pyrazole!-3-carboxylate. British patent 2,227,741 describesrelated benzopyrano 4,3-c!pyrazoles and benzothiopyrano 4,3-c!pyrazoles.European application No. 347,773 similarly describes such fused pyrazolecompounds, and specifically α-cyano-N,1-bis(4-fluorophenyl)-β-oxo-1H-1!benzothieno 3,2-c!pyrazole-3-propanamide. U.S. Pat. No. 5,260,328 toDoria et al describes 2-cyano-3-(1,4-dihydro)-1-phenyl-1!benzothiopyrano 4,3-c!pyrazol-3-yl)-3-oxo-propanamides for thetreatment of rheumatoid arthritis.

U.S. Pat. No. 4,678,499 to Pasteris et al describes1-aryl-indenopyrazol-4-one-5-sulfonamides as having herbicidal activity.Specifically, 1-phenylindenopyrazol-4-one-5-sulfonamide and1,4-dihydro-N-(4-methoxy-6-methyl-2-pyrimidinyl)amino!carbonyl!-3-methyl-1-(4-(methylsulfonyl)phenyl!-4-oxo-indeno1,2-c!pyrazole-5-sulfonamide are described.

The invention's benzopyranopyrazolyl derivatives are found to showusefulness in vivo as antiinflammatory agents with minimal side effects.

DESCRIPTION OF THE INVENTION

A class of compounds useful in treating inflammation-related disordersis defined by Formula I: ##STR2## wherein A is --(CH₂)_(m)--X--(CH₂)_(n) --; wherein X is selected from S(O)_(p), O and NR³ ;

wherein m is 0 to 3, inclusive;

wherein n is 0 to 3, inclusive;

wherein p is 0 to 2, inclusive;

wherein B is selected from aryl and heteroaryl;

wherein R¹ is selected from hydrido, halo, haloalkyl, cyano, nitro,formyl, alkoxycarbonyl, carboxyl, carboxylalkyl, alkoxycarbonylalkyl,amidino, cyanoamidino, aminocarbonyi, alkoxy, alkoxyalkyl,aminocarbonylalkyl, N-alkylaminocarbonyl, N-arylaminocarbonyl,N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylcarbonyl,alkylcarbonylalkyl, hydroxyalkyl, alkylthio, alkylsulfinyl,alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl,N,N-dialkylaminosulfonyl, N-alkyl-N-arylaminosulfonyl and heterocyclic;

wherein R² is selected from aryl and heteroaryl, wherein R² isoptionally substituted at a substitutable position with one or moreradicals selected from alkylsulfonyl, aminosulfonyl, halo, alkyl,alkoxy, hydroxyl and haloalkyl;

wherein R³ is selected from hydrido and alkyl; and

wherein R⁴ is one or more radicals selected from hydrido, halo,alkylthio, alkylsulfinyl, alkyl, alkylsulfonyl, cyano, carboxyl,alkoxycarbonyl, amido, N-alkylaminocarbonyl, N-arylaminocarbonyl,N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, haloalkyl,hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, aminosulfonyl,N-alkylaminosulfonyl, amino, N-alkylamino, N,N-dialkylamino,heterocyclic, nitro and acylamino;

provided either R⁴ is aminosulfonyl or alkylsulfonyl, or R² issubstituted with aminosulfonyl or alkylsulfonyl;

or a pharmaceutically-acceptable salt thereof.

Compounds of Formula I would be useful for, but not limited to, thetreatment of inflammation in a subject, and for treatment of otherinflammation-associated disorders, such as, as an analgesic in thetreatment of pain and headaches, or as an antipyretic for the treatmentof fever. For example, compounds of the invention would be useful totreat arthritis, including but not limited to rheumatoid arthritis,spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupuserythematosus and juvenile arthritis. Such compounds of the inventionwould be useful in the treatment of asthma, bronchitis, menstrualcramps, tendinitis, bursitis, and skin related conditions such aspsoriasis, eczema, burns and dermatitis. Compounds of the invention alsowould be useful to treat gastrointestinal conditions such asinflammatory bowel disease, Crohn's disease, gastritis, irritable bowelsyndrome and ulcerative colitis and for the prevention of colorectalcancer. Compounds of the invention would be useful in treatinginflammation in such diseases as vascular diseases, migraine headaches,periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis,multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,polymyositis, gingivitis, hypersensitivity, conjunctivitis, cysticfibrosis, swelling occurring after injury, myocardial ischemia, and thelike. The compounds would also be useful in the treatment of ophthalmicdiseases such as retinitis, retinopathies, uveitis, and of acute injuryto the eye tissue. The compounds would also be useful for the treatmentof certain central nervous system disorders such as alzheimers diseaseand dementia. The compounds of the invention are useful asanti-inflammatory agents, such as for the treatment of arthritis, withthe additional benefit of having significantly less harmful sideeffects. These compounds would also be useful in the treatment ofallergic rhinitis, respiratory distress syndrome, endotoxin shocksyndrome, atherosclerosis and central nervous system damage resultingfrom stroke, ischemia and trauma.

Besides being useful for human treatment, these compounds are alsouseful for treatment of mammals, including horses, dogs, cats, rats,mice, sheep, and pigs, and of birds.

The present compounds may also be used in co-therapies, partially orcompletely, in place of other conventional antiinflammatories, such astogether with steroids, NSAIDs, 5-lipoxygenase inhibitors, LTB₄antagonists and LTA₄ hydrolase inhibitors.

Suitable LTB₄ inhibitors include, among others, ebselen, BayerBay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark compoundETH-615, Lilly compound LY-293111, Ono compound ONO-4057, Terumocompound TMK-688, Lilly compounds LY-213024, 264086 and 292728, ONOcompound ONO-LB457, Searle compound SC-53228, calcitrol, Lilly compoundsLY-210073, LY223982, LY233469, and LY255283, ONO compound ONO-LB-448,Searle compounds SC-41930, SC-50605 and SC-51146, and SK&F compoundSKF-104493. Preferably, the LTB₄ inhibitors are selected from ebselen,Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark compoundETH-615, Lilly compound LY-293111, Ono compound ONO-4057, and Terumocompound TMK-688.

Suitable 5-LO inhibitors include, among others, masoprocol, tenidap,zileuton, pranlukast, tepoxalin, rilopirox, flezelastine hydrochloride,enazadrem phosphate, and bunaprolast.

The present invention preferably includes compounds which selectivelyinhibit cyclooxygenase-2 over cyclooxygenase-1. Preferably, thecompounds have a cyclooxygenase-2 IC₅₀ of less than about 0.2 μM, andalso have a selectivity ratio of cyclooxygenase-2 inhibition overcyclooxygenase-1 inhibition of at least 50, and more preferably of atleast 100. Even more preferably, the compounds have a cyclooxygenase-1IC₅₀ of greater than about 1 μM, and more preferably of greater than 10μM. Such preferred selectivity may indicate an ability to reduce theincidence of common NSAID-induced side effects.

A preferred class of compounds consists of those compounds of Formula Iwherein A is --(CH₂)_(m) --X--(CH₂)_(n) --; wherein X is selected fromS(O)_(p), O and NR³ ; wherein m is 0 to 3, inclusive; wherein n is 0 to3, inclusive; wherein p is 0 to 2, inclusive; wherein B is selected fromphenyl, naphthyl and five and six membered heteroaryl; wherein R¹ isselected from halo, lower haloalkyl, cyano, nitro, formyl, loweralkoxycarbonyl, lower carboxyalkyl, lower alkoxycarbonylalkyl, amidino,cyanoamidino, lower alkoxy, lower alkoxyalkyl, aminocarbonyl, loweraminocarbonylalkyl, lower N-alkylaminocarbonyl, N-phenylaminocarbonyl,lower N,N-dialkylaminocarbonyl, lower N-alkyl-N-phenylaminocarbonyl,lower alkylcarbonyl, lower alkylcarbonylalkyl, lower hydroxyalkyl, loweralkylthio, lower alkylsulfinyl, lower alkylsulfonyl, loweralkylthioalkyl, lower alkylsulfinylalkyl, lower alkylsulfonylalkyl,lower N-alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl, lowerN,N-dialkylaminosulfonyl, lower N-alkyl-N-phenylaminosulfonyl andfive-seven membered heterocyclic; wherein R² is selected from phenyl andfive or six membered heteroaryl, wherein R² is optionally substituted ata substitutable position with one or more radicals selected from loweralkylsulfonyl, aminosulfonyl, halo, lower alkyl, lower alkoxy, hydroxyland lower haloalkyl; wherein R³ is selected from hydrido and loweralkyl; and wherein R⁴ is one or more radicals selected from hydrido,halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, loweralkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl,lower N-alkylaminocarbonyl, N-phenylaminocarbonyl, lowerN,N-dialkylaminocarbonyl, lower N-alkyl-N-phenylaminocarbonyl, lowerhaloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower haloalkoxy,aminosulfonyl, lower N-alkylaminosulfonyl, amino, lower N-alkylamino,lower N,N-dialkylamino, five-seven membered heterocyclic, nitro andacylamino; or a pharmaceutically-acceptable salt thereof.

A more preferred class of compounds consists of those compounds ofFormula I wherein A is --(CH₂)_(m) --X-- (CH₂)_(n) --; wherein X isS(O)_(p) or O; wherein m is 0, 1 or 2; wherein n is 0, 1 or 2; wherein pis 0, 1 or 2; wherein B is selected from phenyl and five and sixmembered heteroaryl; wherein R¹ is selected from halo, lower haloalkyl,cyano, formyl, lower alkoxycarbonyl, aminocarbonyl, loweralkoxycarbonylalkyl, lower alkoxy, lower alkoxyalkyl, loweraminocarbonylalkyl, lower N-alkylaminocarbonyl, N-phenylaminocarbonyl,lower N,N-dialkylaminocarbonyl, lower N-alkyl-N-phenylaminocarbonyl andlower hydroxyalkyl; wherein R² is phenyl substituted at a substitutableposition with a radical selected from lower alkylsulfonyl andaminosulfonyl; and wherein R⁴ is one or more radicals selected fromhydrido, halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, loweralkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl,lower N-alkylaminocarbonyl, lower N,N-dialkylaminocarbonyl, lowerN-alkyl-N-phenylaminocarbonyl, lower haloalkyl, hydroxyl, lower alkoxy,lower hydroxyalkyl, amino, lower N-alkylamino, lower N,N-dialkylamino,lower haloalkoxy and nitro; or a pharmaceutically-acceptable saltthereof.

An even more preferred class of compounds consists of those compounds ofFormula I wherein A is --(CH₂)_(m) --X-- (CH₂)_(n) --; wherein X isS(O)_(p) or O; wherein m is 0 or 1; wherein n is 0 or 1; wherein p is 0or 1; wherein B is selected from phenyl and five and six memberedheteroaryl; wherein R¹ is selected from lower haloalkyl, lowerhydroxyalkyl, cyano, formyl, lower alkoxycarbonyl, lower alkoxy, lowerN-alkylaminocarbonyl, N-phenylaminocarbonyl, lowerN,N-dialkylaminocarbonyl and lower N-alkyl-N-phenylaminocarbonyl;wherein R² is phenyl substituted at a substitutable position with aradical selected from lower alkylsulfonyl and aminosulfonyl; and whereinR⁴ is one or more radicals selected from hydrido, halo, lower alkylthio,lower alkylsulfinyl, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl,aminocarbonyl, lower haloalkyl, hydroxyl, lower alkoxy, amino, lowerN-alkylamino, lower N,N-dialkylamino, lower hydroxyalkyl and lowerhaloalkoxy; or a pharmaceutically-acceptable salt thereof.

A class of compounds of particular interest consists of those compoundsof Formula I wherein A is --(CH₂)_(m) --X--(CH₂)_(n) --; wherein X isS(O)_(p) or O; wherein m is 0 or 1; wherein n is 0 or 1; wherein p is 0or 1; wherein B is selected from phenyl, thienyl, pyridyl, furyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,thiaimidazolyl, oxoimidazolyl, azaoxazolyl, azathiazolyl and pyrrolyl;wherein R¹ is selected from fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl,dichloropropyl, hydroxymethyl, hydroxyethyl, cyano, formyl, carboxyl,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,pentoxycarbonyl, aminocarbonyl, methoxy, ethoxy, propoxy, n-butoxy,N-methylaminocarbonyl, N-phenylaminocarbonyl, N,N-dimethylaminocarbonyl,N-methyl-N-phenylaminocarbonyl and methylcarbonyl; wherein R² is phenylsubstituted at a substitutable position with a radical selected frommethylsulfonyl and aminosulfonyl; wherein R⁴ is optionally substitutedwith one or more radicals selected from hydrido, fluoro, chloro, bromo,methylthio, ethylthio, isopropylthio, tert-butylthio, isobutylthio,hexylthio, methylsulfinyl, ethylsulfinyl, isopropylsulfinyl,tert-butylsulfinyl, isobutylsulfinyl, hexylsulfinyl, methyl, ethyl,isopropyl, tert-butyl, isobutyl, hexyl, cyano, carboxyl,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,pentoxycarbonyl, aminocarbonyl, fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl,dichlorcpropyl, hydroxyl, methoxy, methylenedioxy, ethoxy, propoxy,n-butoxy, hydroxymethyl and trifluoromethoxy; or apharmaceutically-acceptable salt thereof.

The preferred compounds of Formula I can be represented by FormulasIa-Ip as follows: ##STR3##

A family of specific compounds of particular interest within Formula Iconsists of compounds and pharmaceutically-acceptable salts thereof asshown in the following Tables:

                  TABLE I    ______________________________________    General Structure Ia    R.sup.1        R.sup.2      R.sup.4    ______________________________________    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CF.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CF.sub.2 Cl    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CF.sub.2 CF.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CO.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CO.sub.2 CH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CO.sub.2 C.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CONH.sub.2     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CONHCH.sub.3   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CONH(C.sub.6 H.sub.3)                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CON(CH.sub.3).sub.2                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CON(C.sub.2 H.sub.5).sub.2                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CON(CH.sub.3)(C.sub.2 H.sub.5)                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CON(CH.sub.3)(C.sub.6 H.sub.5)                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H     ##STR4##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H     ##STR5##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CN             C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 OH    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 OCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 OC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 OC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SOCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SOC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SOC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SO.sub.2 CH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SO.sub.2 C.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SO.sub.2 C.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                5-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-Cl    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-C1    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6,7-(OCH.sub.2 O)    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-N(CH.sub.3).sub.2    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                5-F, 6-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                5-Cl, 6-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-Cl, 5-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                5-F, 6-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                5,6-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-SCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                5-F, 6-SCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-SOCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                5-F, 6-SOCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                5-F, 6-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 F                                6-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 Cl                                6-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 OCH.sub.3                                6-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 CH.sub.3                                6-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SOCH.sub.3                                6-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CF.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CF.sub.2 Cl    C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CF.sub.2 CF.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CO.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CO.sub.2 CH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CO.sub.2 C.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CONH.sub.2     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CONHCH.sub.3   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CONH(C.sub.6 H.sub.3)                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CON(CH.sub.3).sub.2                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CON(C.sub.2 H.sub.5).sub.2                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CON(CH.sub.3)(C.sub.2 H.sub.5)                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CON(CH.sub.3)(C.sub.6 H.sub.5)                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H     ##STR6##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H     ##STR7##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CN             C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 OH    C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 OCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 OC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 OC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SOCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SOC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SO.sub.2 CH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SO.sub.2 C.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SO.sub.2 C.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                5-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                7-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                7-Cl    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-Cl    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6,7-(OCH.sub.2 O)    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-N(CH.sub.3).sub.2    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                5-F, 6-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                5-Cl, 6-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-Cl, 5-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                5-F, 6-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                5,6-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-SCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                5-F, 6-SCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-SOCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                5-F, 6-SOCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                5-F, 6-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 F                                6-SO.sub.2 NH.sub.2    CF.sub.3       C.sub.6 H.sub.5 Cl                                6-SO.sub.2 NH.sub.2    CF.sub.3       C.sub.6 H.sub.5 OCH.sub.3                                6-SO.sub.2 NH.sub.2    CF.sub.3       C.sub.6 H.sub.5 CH.sub.3                                6-SO.sub.2 NH.sub.2    CF.sub.3       C.sub.6 H.sub.5 SOCH.sub.3                                6-SO.sub.2 NH.sub.2    CF.sub.3       thienylSO.sub.2 NH.sub.2                                5-F, 6-OCH.sub.3    ______________________________________

                  TABLE II    ______________________________________    General Structure Ib    B               R.sup.2    ______________________________________     ##STR8##       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR9##       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR10##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR11##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR12##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR13##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR14##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR15##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR16##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR17##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR18##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR19##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR20##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR21##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR22##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR23##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR24##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR25##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR26##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR27##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR28##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR29##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2    ______________________________________

                  TABLE III    ______________________________________    General Structure Ic    R.sup.1        R.sup.2      R.sup.4    ______________________________________    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CF.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CF.sub.2 Cl    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CF.sub.2 CF.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CO.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CO.sub.2 CH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CO.sub.2 C.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CONH.sub.2     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CONHCH.sub.3   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CONH(C.sub.6 H.sub.3)                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CON(CH.sub.3).sub.2                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CON(C.sub.2 H.sub.5).sub.2                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CON(CH.sub.3)(C.sub.2 H.sub.5)                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3    CON(CH.sub.3)(C.sub.6 H.sub.5)                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H     ##STR30##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H     ##STR31##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CN             C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 OH    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 OCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 OC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 OC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SOCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SOC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SOC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SO.sub.2 CH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SO.sub.2 C.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SO.sub.2 C.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                5-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-Cl    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-Cl    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6,7-(OCH.sub.2 O)-    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-N(CH.sub.3).sub.2    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                5-F, 6-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                5-Cl, 6-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-Cl, 5-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                5-F, 6-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                5,6-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-SCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                5-F, 6-SCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-SOCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                5-F, 6-SOCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                5-F, 6-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 F                                6-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 Cl                                6-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.5 H.sub.5 OCH.sub.3                                6-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 CH.sub.3                                6-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SOCH.sub.3                                6-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CF.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CF.sub.2 Cl    C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CF.sub.2 CF.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CO.sub.2 H     C.sub.6 H.sub.5.sub.SO.sub.2 NH.sub.2                                H    CO.sub.2 CH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CO.sub.2 C.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CONH.sub.2     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CONHCH.sub.3   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CONH(C.sub.6 H.sub.3)                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CON(CH.sub.3).sub.2                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CON(C.sub.2 H.sub.5).sub.2                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CON(CH.sub.3)(C.sub.2 H.sub.5)                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CON(CH.sub.3)(C.sub.6 H.sub.5)                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H     ##STR32##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H     ##STR33##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CN             C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 OH    C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 OCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 OC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 OC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SOC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SO.sub.2 CH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SO.sub.2 C.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SO.sub.2 C.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                5-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                7-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                7-Cl    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-Cl    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6,7-(OCH.sub.2 O)    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-N(CH.sub.3).sub.2    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                5-F, 6-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                5-Cl, 6-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-Cl, 5-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                5-F, 6-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                5,6-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-SCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                5-F, 6-SCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-SOCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                5-F, 6-SOCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                5-F, 6-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 F                                6-SO.sub.2 NH.sub.2    CF.sub.3       C.sub.6 H.sub.5 Cl                                6-SO.sub.2 NH.sub.2    CF.sub.3       C.sub.6 H.sub.5 OCH.sub.3                                6-SO.sub.2 NH.sub.2    CF.sub.3       C.sub.6 H.sub.5 CH.sub.3                                6-SO.sub.2 NH.sub.2    CF.sub.3       C.sub.6 H.sub.5 SOCH.sub.3                                6-SO.sub.2 NH.sub.2    CF.sub.3       thienylSO.sub.2 NH.sub.2                                5-F, 6-OCH.sub.3    ______________________________________

                  TABLE IV    ______________________________________    General Structure Id    B               R.sup.2    ______________________________________     ##STR34##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR35##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR36##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR37##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR38##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR39##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR40##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR41##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR42##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR43##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR44##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR45##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR46##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR47##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR48##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR49##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR50##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR51##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR52##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR53##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR54##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR55##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2    ______________________________________

                  TABLE V    ______________________________________    General Structure Ie    R.sup.1        R.sup.2      R.sup.4    ______________________________________    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CF.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CF.sub.2 Cl    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CF.sub.2 CF.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CO.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CO.sub.2 CH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CO.sub.2 C.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CONH.sub.2     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CONHCH.sub.3   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CONH(C.sub.6 H.sub.3)                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CON(CH.sub.3).sub.2                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CON(C.sub.2 H.sub.5).sub.2                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CON(CH.sub.3)(C.sub.2 H.sub.5)                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CON(CH.sub.3)(C.sub.6 H.sub.5)                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H     ##STR56##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H     ##STR57##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CN             C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 OH    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 OCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 OC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 OC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SOCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SOC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SOC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SO.sub.2 CH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SO.sub.2 C.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SO.sub.2 C.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                8-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-Cl    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                8-Cl    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7,8-(OCH.sub.2 O)    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-N(CH.sub.3).sub.2    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-F, 7-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-Cl, 7-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-Cl, 6-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-F, 7-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6,7-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-SCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-F, 7-SCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-SOCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-F, 7-SOCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-F, 7-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 F                                7-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 Cl                                7-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 OCH.sub.3                                7-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 CH.sub.3                                7-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SOCH.sub.3                                7-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CF.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CF.sub.2 Cl    C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CF.sub.2 CF.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CO.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CO.sub.2 CH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CO.sub.2 C.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CONH.sub.2     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CONHCH.sub.3   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CONH(C.sub.6 H.sub.3)                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CON(CH.sub.3).sub.2                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CON(C.sub.2 H.sub.5)2                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CON(CH.sub.3)(C.sub.2 H.sub.5)                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CON(CH.sub.3)(C.sub.6 H.sub.5)                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H     ##STR58##     C.sub.6 H.sub.5 SC.sub.2 NH.sub.2                                H     ##STR59##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CN             C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 OH    C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 OCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 OC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 OC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SOCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SOC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SOC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SO.sub.2 CH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SO.sub.2 C.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CH.sub.2 SO.sub.2 C.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                H    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                7-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                8-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                7-Cl    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                8-Cl    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                7,8-(OCH.sub.2 O)    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                7-N(CH.sub.3).sub.2    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                7-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-F, 7-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-Cl, 7-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                7-Cl, 6-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                7-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-F, 7-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6,7-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                7-SCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-F, 7-SCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                7-SOCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-F, 7-SOCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-F, 7-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                6-F, 7-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                7,8,9-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 F                                7-SO.sub.2 NH.sub.2    CF.sub.3       C.sub.6 H.sub.5 Cl                                7-SO.sub.2 NH.sub.2    CF.sub.3       C.sub.6 H.sub.5 OCH.sub.3                                7-SO.sub.2 NH.sub.2    CF.sub.3       C.sub.6 H.sub.5 CH.sub.3                                7-SO.sub.2 NH.sub.2    CF.sub.3       C.sub.6 H.sub.5 SOCH.sub.3                                7-SO.sub.2 NH.sub.2    CF.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                7-CH.sub.3    ______________________________________

                  TABLE VI    ______________________________________    General Structure If    B               R.sup.2    ______________________________________     ##STR60##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR61##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR62##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR63##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR64##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR65##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR66##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR67##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR68##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR69##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR70##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR71##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR72##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR73##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR74##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR75##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR76##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR77##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR78##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR79##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR80##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR81##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR82##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR83##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR84##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR85##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR86##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR87##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR88##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR89##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR90##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR91##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR92##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR93##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR94##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR95##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR96##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR97##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR98##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR99##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR100##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR101##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR102##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR103##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR104##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR105##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR106##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR107##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR108##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR109##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3    ______________________________________

                  TABLE VII    ______________________________________    General Structure Ig    R.sup.1        R.sup.2      R.sup.4    ______________________________________    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CF.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CF.sub.2 Cl    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CF.sub.2 CF.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CO.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CO.sub.2 CH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CO.sub.2 C.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CONH.sub.      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CONHCH.sub.3   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CONH(C.sub.6 H.sub.3)                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CON(CH.sub.3).sub.2                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CON(C.sub.2 H.sub.5).sub.2                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CON(CH.sub.3)(C.sub.2 H.sub.5)                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CON(CH.sub.3)(C.sub.6 H.sub.5)                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H     ##STR110##    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H     ##STR111##    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CN             C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 OH    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 OCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 OC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 OC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SOCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SOC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SOC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SO.sub.2 CH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SO.sub.2 C.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CH.sub.2 SO.sub.2 C.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                H    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                8-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-Cl    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                8-Cl    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7,8-(OCH.sub.2 C)    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-N(CH.sub.3).sub.2    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-F, 7-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-Cl, 7-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-Cl, 6-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-F, 7-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6,7-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-SCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-F, 7-SCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                7-SOCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-F, 7-SOCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                6-F, 7-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 F                                7-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 Cl                                7-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 OCH.sub.3                                7-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 CH.sub.3                                7-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SONH.sub.3                                7-SO.sub.2 CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CF.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CF.sub.2 Cl    C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CF.sub.2 CF.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CO.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CO.sub.2 CH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CO.sub.2 C.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CONH.sub.2     C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CONHCH.sub.3   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CONH(C.sub.6 H.sub.3)                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CON(CH.sub.3).sub.2                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CON(C.sub.2 H.sub.5).sub.2                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CON(CH.sub.3)(C.sub.2 H.sub.5)                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CON(CH.sub.3)(C.sub.6 H.sub.5)                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H     ##STR112##    C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H     ##STR113##    C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CN             C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CH.sub.2 CH    C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CH.sub.2 OCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CH.sub.2 OC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CH.sub.2 OC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CH.sub.2 SCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CH.sub.2 SC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CH.sub.2 SC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CH.sub.2 SOCH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CH.sub.2 SOC.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CH.sub.2 SOC.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CH.sub.2 SO.sub.2 CH.sub.3                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CH.sub.2 SO.sub.2 C.sub.2 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CH.sub.2 SO.sub.2 C.sub.6 H.sub.5                   C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                H    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                6-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                7-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                8-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                7-Cl    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                8-Cl    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                7,8-(OCH.sub.2 O)    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                7-N(CH.sub.3).sub.2    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                7-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                6-F, 7-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                6-Cl, 7-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                7-Cl, 6-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                7-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                6-F, 7-CH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                6,7-F    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                7-SCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                6-F, 7-SCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                7-SOCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                6-F, 7-SOCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                6-F, 7-CH.sub.3    CF.sub.3    thienylSO.sub.2 NH.sub.2                   6-F, 7-OCH.sub.3    CF.sub.3       C.sub.6 H.sub.5 F                                7-SO.sub.2 NH.sub.2    CF.sub.3       C.sub.6 H.sub.5 Cl                                7-SO.sub.2 NH.sub.2    CF.sub.3       C.sub.6 H.sub.5 OCH.sub.3                                7-SO.sub.2 NH.sub.2    CF.sub.3       C.sub.6 H.sub.5 CH.sub.3                                7-SO.sub.2 NH.sub.2    CF.sub.3       C.sub.6 H.sub.5 SOCH.sub.3                                7-SO.sub.2 NH.sub.2    ______________________________________

                  TABLE VIII    ______________________________________    General Structure Ih    B               R.sup.2    ______________________________________     ##STR114##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR115##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR116##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR117##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR118##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR119##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR120##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR121##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR122##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR123##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR124##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR125##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR126##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR127##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR128##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR129##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR130##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR131##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR132##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR133##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR134##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR135##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR136##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR137##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR138##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR139##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR140##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR141##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR142##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR143##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR144##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR145##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR146##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR147##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR148##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR149##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR150##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR151##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR152##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR153##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR154##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR155##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR156##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR157##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR158##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR159##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR160##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR161##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR162##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR163##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2    ______________________________________

                  TABLE IX    ______________________________________    General Structure Ii    p   R.sup.1      R.sup.2         R.sup.4    ______________________________________    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CF.sub.2 H   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CF.sub.2 Cl  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CF.sub.2 CF.sub.3                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CO.sub.2 H   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CO.sub.2 CH.sub.3                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CO.sub.2 C.sub.2 H.sub.5                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CONH.sub.2   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CONHCH.sub.3 C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CONH(C.sub.6 H.sub.3)                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CON(CH.sub.3).sub.2                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CON(C.sub.2 H.sub.5).sub.2                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CON(CH.sub.3)                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3        (C.sub.2 H.sub.5)    0   CON(CH.sub.3)                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H        (C.sub.6 H.sub.5)         ##STR164##  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H         ##STR165##  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CN           C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CH.sub.2 OH  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CH.sub.2 OCH.sub.3                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CH.sub.2 OC.sub.2 H.sub.5                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CH.sub.2 OC.sub.6 H.sub.5                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CH.sub.2 SCH.sub.3                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CH.sub.2 SC.sub.2 H.sub.5                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CH.sub.2 SC.sub.6 H.sub.5                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CH.sub.2 SOCH.sub.3                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CH.sub.2 SOC.sub.2 H.sub.5                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CH.sub.2 SOC.sub.6 H.sub.5                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CH.sub.2 SO.sub.2 CH.sub.3                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CH.sub.2 SO.sub.2 C.sub.2 H.sub.5                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CH.sub.2 SO.sub.2 C.sub.6 H.sub.5                     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     H    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     6-F    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     7-F    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     8-F    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     7-Cl    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     8-Cl    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     7,8-(OCH.sub.2 O)    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     7-N(CH.sub.3).sub.2    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     7-OCH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     6-F, 7-OCH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     6-Cl, 7-OCH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     7-Cl, 6-F    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     7-CH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     6-F, 7-CH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     6,7-F    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     7-SCH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     6-F, 7-SCH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     7-SOCH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     6-F, 7-SOCH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                     6-F, 7-CH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 F                                     7-SO.sub.2 CH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 Cl                                     7-SO.sub.2 CH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 OCH.sub.3                                     7-SO.sub.2 CH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 CH.sub.3                                     7-SO.sub.2 CH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SOCH.sub.3                                     7-SO.sub.2 CH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CF.sub.2 H   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CF.sub.2 H   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     7-F    0   CF.sub.2 H   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     7-CH.sub.3    0   CF.sub.2 H   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     7-Cl    0   CF.sub.2 Cl  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CF.sub.2 CF.sub.3                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CO.sub.2 H   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CO.sub.2 CH.sub.3                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CO.sub.2 C.sub.2 H.sub.5                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CONH.sub.2   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CONHCH.sub.3 C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CONH(C.sub.6 H.sub.3)                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CON(CH.sub.3).sub.2                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CON(C.sub.2 H.sub.5).sub.2                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CON(CH.sub.3)                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H        (C.sub.2 H.sub.5)    0   CON(CH.sub.3)                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H        (C.sub.6 H.sub.5)         ##STR166##  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H         ##STR167##  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CN           C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CN           C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     7-F    0   CN           C.sub.6 H.sub.5 SO.sub.2 NCHN(CH.sub.3).sub.2                                     7-F    0   CH.sub.2 OH  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CH.sub.2 OH  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     7-F    0   CH.sub.2 OCH.sub.3                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CH.sub.2 OC.sub.2 H.sub.5                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CH.sub.2 OC.sub.6 H.sub.5                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CH.sub.2 SCH.sub.3                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CH.sub.2 SC.sub.2 H.sub.5                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CH.sub.2 SC.sub.6 H.sub.5                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CH.sub.2 SOCH.sub.3                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CH.sub.2 SOC.sub.2 H.sub.5                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CH.sub.2 SOC.sub.6 H.sub.5                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CH.sub.2 SO.sub.2 CH.sub.3                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CH.sub.2 SO.sub.2 C.sub.2 H.sub.5                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CH.sub.2 SO.sub.2 C.sub.6 H.sub.5                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     H    0   CONH.sub.2   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     7-F    0   CO.sub.2 CH.sub.3                     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     7-F    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     6-F    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     7-F    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     8-F    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     7-Cl    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     8-Cl    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     7,8-(OCH.sub.2 O)    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     6,7-(OCH.sub.2 O)    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     7-N(CH.sub.3).sub.2    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     7-OCH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     6-F, 7-OCH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     6,8-F, 7-OCH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     6-Cl, 7-OCH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     7-Cl, 6-F    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     7-CH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     6-F, 7-CH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     6,7-F    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     7-SCH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     6-F, 7-SCH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     7-SOCH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     6-F, 7-SOCH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     6-Cl, 7-CH.sub.3    0   CF.sub.3     thienylSO.sub.2 NH.sub.2                                     6-F, 7-OCH.sub.3    0   CF.sub.3     C.sub.6 H.sub.5 F                                     7-SO.sub.2 NH.sub.2    0   CF.sub.3     C.sub.6 H.sub.5 Cl                                     7-SO.sub.2 NH.sub.2    0   CF.sub.3     C.sub.6 H.sub.5 OCH.sub.3                                     7-SO.sub.2 NH.sub.2    0   CF.sub.3     C.sub.6 H.sub.5 CH.sub.3                                     7-SO.sub.2 NH.sub.2    0   CF.sub.3     C.sub.6 H.sub.5 SOCH.sub.3                                     7-SO.sub.2 NH.sub.2    0   CHF.sub.2    C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     6-F, 7-OCH.sub.3    1   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     6-F, 7-OCH.sub.3    1   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     6-Cl, 7-OCH.sub.3    1   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     7-Cl, 6-F    1   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     6-F, 7-CH.sub.3    1   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     6,7-F    1   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     6-F, 7-SCH.sub.3    1   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     6-F, 7-SOCH.sub.3    1   CF.sub.3     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                     6-Cl, 7-CH.sub.3    ______________________________________

                  TABLE X    ______________________________________    General Structure Ij    b                R.sup.2     p    ______________________________________     ##STR168##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR169##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR170##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR171##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR172##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR173##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR174##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR175##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR176##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR177##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR178##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR179##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR180##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR181##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR182##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR183##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR184##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR185##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR186##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR187##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR188##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR189##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR190##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR191##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR192##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR193##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR194##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR195##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR196##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR197##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR198##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR199##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR200##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR201##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR202##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR203##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR204##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR205##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR206##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR207##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR208##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR209##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR210##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR211##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR212##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR213##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR214##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR215##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR216##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR217##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 0     ##STR218##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.2                                 1    ______________________________________

                  TABLE XI    ______________________________________    General Structure Ik    p   R.sup.1        R.sup.2      R.sup.4    ______________________________________    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CF.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CF.sub.2 Cl    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CF.sub.2 CF.sub.3                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CO.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CO.sub.2 CH.sub.3                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CO.sub.2 C.sub.2 H.sub.5                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CONH.sub.2     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CONHCH.sub.3   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CONH(C.sub.6 H.sub.3)                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CON(CH.sub.3).sub.2                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CON(C.sub.2 H.sub.5).sub.2                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CON(CH.sub.3)(C.sub.2 H.sub.5)                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CON(CH.sub.3)(C.sub.6 H.sub.5)                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H         ##STR219##    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H         ##STR220##    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CN             C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CH.sub.2 OH    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CH.sub.2 OCH.sub.3                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CH.sub.2 OC.sub.2 H.sub.5                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CH.sub.2 OC.sub.6 H.sub.5                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CH.sub.2 SCH.sub.3                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CH.sub.2 SC.sub.2 H.sub.5                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CH.sub.2 SC.sub.6 H.sub.5                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CH.sub.2 SOCH.sub.3                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CH.sub.2 SOC.sub.2 H.sub.5                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CH.sub.2 SOC.sub.6 H.sub.5                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CH.sub.2 SO.sub.2 CH.sub.3                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CH.sub.2 SO.sub.2 C.sub.2 H.sub.5                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CH.sub.2 SO.sub.2 C.sub.6 H.sub.5                       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    H    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    6-F    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    7-F    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    8-F    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    7-Cl    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    8-Cl    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    7,8-(OCH.sub.2 O)    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    7-N(CH.sub.3).sub.2    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    7-OCH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    6-F, 7-OCH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    6-Cl, 7-OCH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    7-Cl, 6-F    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    7-CH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    6-F, 7-CH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    6,7-F    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    7-SCH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    6-F, 7-SCH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    7-SOCH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    6-F, 7-SOCH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                    6-F, 7-CH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 F                                    7-SO.sub.2 CH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 Cl                                    7-SO.sub.2 CH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 OCH.sub.3                                    7-SO.sub.2 CH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 CH.sub.3                                    7-SO.sub.2 CH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SOCH.sub.3                                    7-SO.sub.2 CH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CF.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CF.sub.2 Cl    C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CF.sub.2 CF.sub.3                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CO.sub.2 H     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CO.sub.2 CH.sub.3                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CO.sub.2 C.sub.2 H.sub.5                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CONH.sub.2     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CONHCH.sub.3   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CONH(C.sub.6 H.sub.3)                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CON(CH.sub.3).sub.2                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CON(C.sub.2 H.sub.5).sub.2                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CON(CH.sub.3)(C.sub.2 H.sub.5)                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CON(CH.sub.3)(C.sub.6 H.sub.5)                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H         ##STR221##    C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H         ##STR222##    C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CN             C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CH.sub.2 OH    C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CH.sub.2 OCH.sub.3                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CH.sub.2 OC.sub.2 H.sub.5                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CH.sub.2 OC.sub.6 H.sub.5                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CH.sub.2 SCH.sub.3                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CH.sub.2 SC.sub.2 H.sub.5                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CH.sub.2 SC.sub.6 H.sub.5                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CH.sub.2 SOCH.sub.3                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CH.sub.2 SOC.sub.2 H.sub.5                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CH.sub.2 SOC.sub.6 H.sub.5                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CH.sub.2 SO.sub.2 CH.sub.3                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CH.sub.2 SO.sub.2 C.sub.2 H.sub.5                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CH.sub.2 SO.sub.2 C.sub.6 H.sub.5                       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    H    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    6-F    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    7-F    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    8-F    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    7-Cl    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    8-Cl    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    7,8-(OCH.sub.2 O)    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    7-N(CH.sub.3).sub.2    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    7-OCH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    7,8-OCH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    6-F, 7-OCH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    6-Cl, 7-OCH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    7-Cl, 6-F    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    6-CH(CH.sub.3).sub.2    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    7-CH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    6-F, 7-CH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    6,7-F    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    6,7-Cl    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    7-SCH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    6-F, 7-SCH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    7-SOCH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    6-F, 7-SOCH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    6-Cl, 7-CH.sub.3    0   CF.sub.3       thienylSO.sub.2 NH.sub.2                                    6-F, 7-OCH.sub.3    0   CF.sub.3       C.sub.6 H.sub.5 F                                    7-SO.sub.2 NH.sub.2    0   CF.sub.3       C.sub.6 H.sub.5 Cl                                    7-SO.sub.2 NH.sub.2    0   CF.sub.3       C.sub.6 H.sub.5 OCH.sub.3                                    7-SO.sub.2 NH.sub.2    0   CF.sub.3       C.sub.6 H.sub.5 CH.sub.3                                    7-SO.sub.2 NH.sub.2    0   CF.sub.3       C.sub.6 H.sub.5 SOCH.sub.3                                    7-SO.sub.2 NH.sub.2    1   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    6-F, 7-OCH.sub.3    1   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    6-Cl, 7-OCH.sub.3    1   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    7-Cl, 6-F    1   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    6-F, 7-CH.sub.3    1   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    6,7-F    1   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    6-F, 7-SCH.sub.3    1   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    6-F, 7-SOCH.sub.3    1   CF.sub.3       C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                    6-Cl, 7-CH.sub.3    ______________________________________

                  TABLE XII    ______________________________________    General Structure Il    B                R.sup.2     p    ______________________________________     ##STR223##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR224##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR225##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR226##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR227##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR228##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR229##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR230##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR231##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR232##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR233##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR234##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR235##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR236##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR237##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR238##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR239##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR240##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR241##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR242##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR243##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR244##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR245##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR246##      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                                 0     ##STR247##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR248##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR249##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR250##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR251##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR252##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR253##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR254##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR255##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR256##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR257##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR258##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR259##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR260##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR261##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR262##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR263##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR264##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR265##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR266##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR267##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR268##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR269##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR270##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.3                                 0     ##STR271##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                 0     ##STR272##      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                                 0    ______________________________________

                  TABLE XIII    ______________________________________    General Structure Im    R.sup.1       R.sup.2      R.sup.4    ______________________________________    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CF.sub.2 H    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CF.sub.2 Cl   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CF.sub.2 CF.sub.3                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CO.sub.2 H    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CO.sub.2 CH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CO.sub.2 C.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CONH.sub.2    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CONHCH.sub.3  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CONH(C.sub.6 H.sub.3)                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CON(CH.sub.3).sub.2                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CON(C.sub.2 H.sub.5)2                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CON(CH.sub.3)(C.sub.2 H.sub.5)                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CON(CH.sub.3)(C.sub.6 H.sub.5)                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H     ##STR273##   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H     ##STR274##   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CN            C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 OH   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 OCH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 OC.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 OC.sub.6 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 SCH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 SC.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 SC.sub.6 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 SOCH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 SOC.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 SOC.sub.6 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 SO.sub.2 CH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 SO.sub.2 C.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 SO.sub.2 C.sub.6 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               7-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               8-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               9-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               8-Cl    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               9-Cl    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               8,9-(OCH.sub.2 O)    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               8-N(CH.sub.3).sub.2    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               8-OCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               7-F, 8-OCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               7-Cl, 8-OCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               8-Cl, 7-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               8-CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               7-F, 8-CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               7,8-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               8-SCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               7-F, 8-SCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               8-SOCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               7-F, 8-SOCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               7-F, 8-CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 F                               8-SO.sub.2 CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 Cl                               8-SO.sub.2 CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 OCH.sub.3                               8-SC.sub.2 CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 CH.sub.3                               8-SO.sub.2 CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SOCH.sub.3                               8-SO.sub.2 CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CF.sub.2 H    C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CF.sub.2 Cl   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CF.sub.2 CF.sub.3                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CO.sub.2 H    C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CO.sub.2 CH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CO.sub.2 C.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CONH.sub.2    C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CONHCH.sub.3  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CONH(C.sub.6 H.sub.3)                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CON(CH.sub.3).sub.2                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CON(C.sub.2 H.sub.5).sub.2                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CON(CH.sub.3)(C.sub.2 H.sub.5)                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CON(CH.sub.3)(C.sub.6 H.sub.5)                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H     ##STR275##   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H     ##STR276##   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CN            C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 OH   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 OCH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 OC.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 OC.sub.6 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 SCH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 SC.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 SC.sub.6 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 SOCH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 SOC.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 SOC.sub.6 HS                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 SO.sub.2 CH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 SO.sub.2 C.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 SO.sub.2 C.sub.6 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               7-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               8-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               9-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               7,8-(OCH.sub.2 O)    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               8-N(CH.sub.3).sub.2    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               8-OCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               7-F, 8-OCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               7-Cl, 8-OCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               8-Cl, 7-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               8-CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               7-F, 8-CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               7,8-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               8-SCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               7-F, 8-SCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               8-SOCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               7-F, 8-SOCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               7-F, 8-CH.sub.3    CF.sub.3      thienylSO.sub.2 NH.sub.2                               7-F, 9OCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 F                               8-SO.sub.2 NH.sub.2    CF.sub.3      C.sub.6 H.sub.5 Cl                               8-SO.sub.2 NH.sub.2    CF.sub.3      C.sub.6 H.sub.5 OCH.sub.3                               8-SO.sub.2 NH.sub.2    CF.sub.3      C.sub.6 H.sub.5 CH.sub.3                               8-SO.sub.2 NH.sub.2    CF.sub.3      C.sub.6 H.sub.5 SOCH.sub.3                               8-SO.sub.2 NH.sub.2    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               8-Cl    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               9-Cl    ______________________________________

                  TABLE XIV    ______________________________________    General Structure In    B               R.sup.2    ______________________________________     ##STR277##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR278##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR279##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR280##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR281##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR282##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR283##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR284##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR285##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR286##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR287##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR288##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR289##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR290##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR291##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR292##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR293##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR294##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR295##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR296##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR297##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR298##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3    ______________________________________

                  TABLE XV    ______________________________________    General Structure Io    R.sup.1       R.sup.2      R.sup.4    ______________________________________    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CF.sub.2 H    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CF.sub.2 Cl   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CF.sub.2 CF.sub.3                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CO.sub.2 H    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CO.sub.2 CH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CO.sub.2 C.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CONH.sub.2    C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CONHCH.sub.3  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CONH(C.sub.6 H.sub.3)                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CON(CH.sub.3).sub.2                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CON(C.sub.2 H.sub.5)2                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CON(CH.sub.3)(C.sub.2 H.sub.5)                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CON(CH.sub.3)(C.sub.6 H.sub.5)                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H     ##STR299##   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H     ##STR300##   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CN            C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 OH   C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 OCH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 OC.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 OC.sub.6 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 SCH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 SC.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 SC.sub.6 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 SOCH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 SOC.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 SOC.sub.6 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 SO.sub.2 CH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 SO.sub.2 C.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CH.sub.2 SO.sub.2 C.sub.6 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               H    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               7-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               8-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               9-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               8-Cl    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               9-Cl    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               8,9-(OCH.sub.2 O)    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               8-N(CH.sub.3).sub.2    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               8-OCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               7-F, 8-OCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               7-Cl, 8-OCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               8-Cl, 7-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               8-CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               7-F, 8-CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               7,8-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               8-SCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               7-F, 8-SCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               8-SOCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               7-F, 8-SOCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 CH.sub.3                               7-F, 8-CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 F                               8-SO.sub.2 CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 Cl                               8-SO.sub.2 CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 OCH.sub.3                               8-SC.sub.2 CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 CH.sub.3                               8-SO.sub.2 CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SOCH.sub.3                               8-SO.sub.2 CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CF.sub.2 H    C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CF.sub.2 Cl   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CF.sub.2 CF.sub.3                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CO.sub.2 H    C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CO.sub.2 CH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CO.sub.2 C.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CONH.sub.2    C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CONHCH.sub.3  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CONH(C.sub.6 H.sub.3)                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CON(CH.sub.3).sub.2                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CON(C.sub.2 H.sub.5).sub.2                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CON(CH.sub.3)(C.sub.2 H.sub.5)                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CON(CH.sub.3)(C.sub.6 H.sub.5)                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H     ##STR301##   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H     ##STR302##   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CN            C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 OH   C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 OCH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 OC.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 OC.sub.6 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 SCH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 SC.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 SC.sub.6 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 SOCH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 SOC.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 SOC.sub.6 HS                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 SO.sub.2 CH.sub.3                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 SO.sub.2 C.sub.2 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CH.sub.2 SO.sub.2 C.sub.6 H.sub.5                  C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               H    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               7-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               8-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               9-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               8-Cl    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               9-Cl    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               7,8-(OCH.sub.2 O)    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               8-N(CH.sub.3).sub.2    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               8-OCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               7-F, 8-OCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               7-Cl, 8-OCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               8-Cl, 7-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               8-CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               7-F, 8-CH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               7,8-F    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               8-SCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               7-F, 8-SCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               8-SOCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               7-F, 8-SOCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 SO.sub.2 NH.sub.2                               7-F, 8-CH.sub.3    CF.sub.3      thienylSO.sub.2 NH.sub.2                               7-F 8-OCH.sub.3    CF.sub.3      C.sub.6 H.sub.5 F                               8-SO.sub.2 NH.sub.2    CF.sub.3      C.sub.6 H.sub.5 Cl                               8-SO.sub.2 NH.sub.2    CF.sub.3      C.sub.6 H.sub.5 OCH.sub.3                               8-SO.sub.2 NH.sub.2    CF.sub.3      C.sub.6 H.sub.5 CH.sub.3                               8-SO.sub.2 NH.sub.2    CF.sub.3      C.sub.6 H.sub.5 SOCH.sub.3                               8-SO.sub.2 NH.sub.2    ______________________________________

                  TABLE XVI    ______________________________________    General Structure Ip    B               R.sup.2    ______________________________________     ##STR303##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR304##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR305##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR306##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR307##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR308##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR309##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR310##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR311##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR312##     C.sub.6 H.sub.5 SO.sub.2 CH.sub.3     ##STR313##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR314##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR315##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR316##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR317##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR318##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR319##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR320##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR321##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR322##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR323##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2     ##STR324##     C.sub.6 H.sub.5 SO.sub.2 NH.sub.2    ______________________________________

Within Formula I there is a subclass of compounds of high interestrepresented by Formula II: ##STR325## wherein A is --(CH₂)_(m)--O--(CH₂)_(n) -- or --(CH₂)_(m) --S(O)_(p) -- (CH₂)_(n) --; wherein mis 0 or 1; wherein n is 0 or 1; wherein p is 0 or 1; wherein B isselected from aryl and heteroaryl; wherein R¹ is selected fromhaloalkyl, hydroxyalkyl, aminocarbonyl, alkoxycarbonyl and cyano;wherein R⁴ is one or more radicals selected from hydrido, halo, alkyland alkoxy; and wherein R⁵ is selected from alkyl and amino; or apharmaceutically-acceptable salt thereof.

A preferred class of compounds consists of those compounds of Formula IIwherein A is --(CH₂)_(m) --O--(CH₂)_(n) -- or --(CH₂)_(m) --S(O)_(p)--(CH₂)_(n) --; wherein m is 0 or 1; wherein n is 0 or 1; wherein p is 0or 1; wherein B is selected from phenyl and five membered heteroaryl;wherein R¹ is selected from lower haloalkyl, lower hydroxyalkyl,aminocarbonyl, lower alkoxycarbonyl and cyano; wherein R⁴ is one or moreradicals selected from hydrido, halo, lower alkyl and lower alkoxy; andwherein R⁵ is selected from lower alkyl and amino; or apharmaceutically-acceptable salt thereof.

A class of compounds of particular interest consists of those compoundsof Formula II wherein A is --(CH₂)_(m) --O--(CH₂)_(n) -- or --(CH₂)_(m)--S(O)_(p) --(CH₂)_(n) --; wherein m is 0 or 1; wherein n is 0 or 1;wherein p is 0 or 1; wherein B is selected from phenyl, thienyl, furyland pyrrolyl; wherein R¹ is selected from fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl,dichloropropyl, hydroxymethyl, hydroxyethyl, aminocarbonyl,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl andcyano; wherein R⁴ is one or more radicals selected from hydrido, fluoro,chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, hexyl,methoxy, methylenedioxy, ethoxy, propoxy, n-butoxy and tert-butoxy; andwherein R⁵ is selected from methyl and amino; or apharmaceutically-acceptable salt thereof.

A family of specific compounds of particular interest within Formula IIconsists of compounds and pharmaceutically-acceptable salts thereof asfollows:

4- 3-(difluoromethyl)-1,5-dihydro-7-methyl- 2!benzopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

7-fluoro-1,5-dihydro-1- 4-(methylsulfonyl)phenyl!-3-(trifluoromethyl)-2!benzothiopyrano 4,3-c!pyrazole;

4- 1,5-dihydro-7,8,9-trimethoxy-3-(trifluoromethyl)- 2!benzopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 6,8-difluoro-1,5-dihydro-7-methoxy-3-(trifluoromethyl)-2!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 3-cyano-7-fluoro-1,5-dihydro- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 3-(difluoromethyl)-7-fluoro-1,5-dihydro- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 1,5-dihydro-7-methyl-3-(trifluoromethyl)- 2!benzopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 3-cyano-7-fluoro-1,5-dihydro- 2!benzothiopyrano4,3-c!pyrazol-1-yl!-N- (dimethylamino)methylene!benzenesulfonamide;

4- 3-(difluoromethyl)-1,5-dihydro-7-methyl- 2!benzenethiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 7-fluoro-1,5-dihydro-3-(hydroxymethyl)- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 1,5-dihydro-3-(trifluoromethyl)- 1,3!dioxolo 6,7! 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 1,5-dihydro-7-methoxy-3-(trifluoromethyl)- 2!benzopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 7-chloro-3-(difluoromethyl)-1,5-dihydro- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 7-chloro-1,5-dihydro-3-trifluoromethyl-thieno3',2':4,5!thiopyrano-s-oxide 3,2-c!pyrazol-1-yl!benzenesulfonamide;

methyl1-(4-aminosulfonylphenyl)-1,5-dihydro-7-fluoro-3-(trifluoromethyl)-2!benzothiopyrano 4,3-c!pyrazol-3-yl!carboxylate;

1-(4-aminosulfonylphenyl)-1,5-dihydro-7-fluoro-3-(trifluoromethyl)-2!benzothiopyrano 4,3-c!pyrazol-3-yl!carboxamide;

4- 1,5-dihydro-6-fluoro-7-methoxy-3-(difluoromethyl)- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 1,5-dihydro-7-fluoro-3-(trifluoromethyl)- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 1,5-dihydro-6-fluoro-7-methoxy-3-(trifluoromethyl)- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

1,5-dihydro-6-fluoro-7-methoxy-1-4-(methylsulfonyl)phenyl!-3-(trifluoromethyl)- 2!benzothiopyrano4,3-c!pyrazole;

4- 1,4-dihydro-3-(trifluoromethyl)- 1!benzopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

methyl 1- 4-(aminosulfonyl)phenyl!-1,4-dihydro- 1!benzopyrano4,3-c!pyrazol-3-yl!carboxylate;

4- 1,4-dihydro-6-fluoro-3-(trifluoromethyl)- 1!benzopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 3-(trifluoromethyl)-1H-benzofuro3,2-c!pyrazol-1-yl!benzenesulfonamide;

4- 1,4-dihydro-3-(trifluoromethyl)- 1!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

methyl 1- 4-(aminosulfonyl)phenyl!-1,4-dihydro- 1!benzothiopyrano4,3-c!pyrazol-3-carboxylate;

4- 6,7-dichloro-1,4-dihydro-3-(trifluoromethyl)- 1!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 1,4-dihydro-7-fluoro-3-(trifluoromethyl)- 1!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 1,4-dihydro-6-isopropyl-3-(trifluoromethyl)- 1!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 1,4-dihydro-7,8-dimethoxy-3-(trifluoromethyl)- 1!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 1,4-dihydro-7-methoxy-3-(trifluoromethyl)- 1!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 1,4-dihydro-7-methyl-3-(trifluoromethyl)- 1!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 7-chloro-1,4-dihydro-3-(trifluoromethyl)- 1!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 1,5-dihydro-3-(trifluoromethyl)- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 1,5-dihydro-7-methyl-3-(trifluoromethyl)- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

1,5-dihydro-1- 4-(methylsulfonyl)phenyl!-7-methyl-3-(trifluoromethyl)-2!benzothiopyrano 4,3-c!pyrazole;

4- 7-chloro-1,5-dihydro-3-(trifluoromethyl)- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 1,5-dihydro-7-methoxy-3-(trifluoromethyl)- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide;

4- 7-chloro-1,5-dihydro-3-trifluoromethyl- 2!thienothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide; and

4- 3-cyano-1,4-dihydro 1!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide.

The term "hydrido" denotes a single hydrogen atom (H). This hydridoradical may be attached, for example, to an oxygen atom to form ahydroxyl radical or two hydrido radicals may be attached to a carbonatom to form a methylene (--CH₂ --) radical. Where used, either alone orwithin other terms such as "haloalkyl", "alkylsulfonyl", "alkoxyalkyl"and "hydroxyalkyl", the term "alkyl" embraces linear or branchedradicals having one to about twenty carbon atoms or, preferably, one toabout twelve carbon atoms. More preferred alkyl radicals are "loweralkyl" radicals having one to about ten carbon atoms. Most preferred arelower alkyl radicals having one to about six carbon atoms. Examples ofsuch radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.The term "halo" means halogens such as fluorine, chlorine, bromine oriodine. The term "haloalkyl" embraces radicals wherein any one or moreof the alkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals. A monohaloalkyl radical, for one example, may have either aniodo, bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. "Lower haloalkyl" embracesradicals having 1-6 carbon atoms. Examples of haloalkyl radicals includefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. Theterm "hydroxyalkyl" embraces linear or branched alkyl radicals havingone to about ten carbon atoms any one of which may be substituted withone or more hydroxyl radicals. More preferred hydroxyalkyl radicals are"lower hydroxyalkyl" radicals having one to six carbon atoms and one ormore hydroxyl radicals. Examples of such radicals include hydroxymethyl,hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms"alkoxy" and "alkoxyalkyl" embrace linear or branched oxy-containingradicals each having alkyl portions of one to about ten carbon atoms.More preferred alkoxy radicals are "lower alkoxyl" radicals having oneto six carbon atoms. Examples of such radicals include methoxy, ethoxy,propoxy, butoxy and tert-butoxy. The term "alkoxyalkyl" embraces alkylradicals having one or more alkoxy radicals attached to the alkylradical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.More preferred alkoxyalkyl radicals are "lower alkoxyalkyl" radicalshaving one to six carbon atoms and one or two alkoxy radicals. Examplesof such radicals include methoxymethyl, methoxyethyl, ethoxyethyl,methoxybutyl and methoxypropyl. The "alkoxy" or "alkoxyalkyl" radicalsmay be further substituted with one or more halo atoms, such as fluoro,chloro or bromo, to provide "haloalkoxy" or haloalkoxyalkyl radicals.More preferred haloalkoxy radicals are "lower haloalkoxy" radicalshaving one to six carbon atoms and one or more halo radicals. Examplesof such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term "aryl", aloneor in combination, means a carbocyclic aromatic system containing one,two or three rings wherein such rings may be attached together in apendent manner or may be fused. The term "aryl" embraces aromaticradicals such as phenyl, naphthyl, tetrahydronaphthyl, indane andbiphenyl. The term "heterocyclic" embraces saturated, partiallysaturated and unsaturated heteroatom-containing ring-shaped radicals,where the heteroatoms may be selected from nitrogen, sulfur and oxygen.Such heterocyclic radicals preferrably include ring systems having 3 to10 members. Examples of saturated heterocyclic radicals includesaturated 3 to 6-membered heteromonocylic group containing 1 to 4nitrogen atoms e.g. pyrrolidinyl, imidazolidinyl, piperidino,piperazinyl, etc.!; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g.morpholinyl, etc.!; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g.,thiazolidinyl, etc.!. Examples of partially saturated heterocyclicradicals include dihydrothiophene, dihydropyran, dihydrofuran anddihydrothiazole. Examples of unsaturated heterocyclic radicals, alsotermed "heteroaryl" radicals, include unsaturated 3 to 6 memberedheteromonocyclic group containing 1 to 4 nitrogen atoms, for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazolyl e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.! tetrazolyl e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.!, etc.; unsaturated condensedheterocyclic group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl e.g., tetrazolo1,5-b!pyridazinyl, etc.!, etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupcontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyle.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.!etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms e.g. benzoxazolyl, benzoxadiazolyl,etc.!; unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.! and isothiazolyl; unsaturated condensedheterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogenatoms e.g., benzothiazolyl, benzothiadiazolyl, etc.! and the like. Theterm also embraces radicals where heterocyclic radicals are fused witharyl radicals. Examples of such fused bicyclic radicals includebenzofuryl, benzothienyl, and the like. Said "heterocyclic" radicals mayhave 1 to 3 substituents such as lower alkyl, hydroxy, oxo, amino andlower alkylamino. More preferred heteroaryl radicals include five to sixmembered heteroaryl radicals. The term "alkylthio" embraces radicalscontaining a linear or branched alkyl radical, of one to about tencarbon atoms attached to a divalent sulfur atom. More preferredalkylthio radicals are "lower alkylthio" radicals having alkyl radicalsof one to six carbon atoms. Examples of such lower alkylthio radicalsare methylthio, ethylthio, propylthio, butylthio and hexylthio. The term"alkylthioalkyll" embraces alkylthio radicals attached to an alkylradical. More preferred alkylthioalkyl radicals are "loweralkylthioalkyl" radicals having alkyl radicals of one to six carbonatoms and an alkylthio radical as described above. Examples of suchradicals include methylthiomethyl. The term "arylthiol" embracesradicals containing an aryl radical, attached to a divalent sulfur atom,such as a phenylthio radical. The term "alkylsulfinyl" embraces radicalscontaining a linear or branched alkyl radical, of one to ten carbonatoms, attached to a divalent --S(═O)-- radical. More preferredalkylsulfinyl radicals are "lower alkylsulfinyl" radicals having one tosix carbon atoms. Examples of such lower alkylsulfinyl radicals includemethylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The term"alkylsulfinylalkyl" embraces alkylsulfinyl radicals attached to analkyl radical, where alkyl and alkylsulfinyl are defined as above. Morepreferred alkylsulfinylalkyl radicals are "lower alkylsulfinylalkyl"radicals having one to six carbon atoms. Examples of such loweralkylsulfinylalkyl radicals include methylsulfinylmethyl. The term"sulfonyl", whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals --SO₂ --."Alkylsulfonyl" embraces alkyl radicals attached to a sulfonyl radical,where alkyl is defined as above. More preferred alkylsulfonyl radicalsare "lower alkylsulfonyl" radicals having one to six carbon atoms.Examples of such lower alkylsulfonyl radicals include methylsulfonyl,ethylsulfonyl and propylsulfonyl. The term "alkylsulfonylalkyl" embracesalkylsulfonyl radicals attached to an alkyl radical, where alkyl andalkylsulfonyl are defined as above. More preferred alkylsulfonylalkylradicals are "lower alkylsulfonylalkyl" radicals having one to sixcarbon atoms. Examples of such lower alkylsulfonylalkyl radicals includemethylsulfonylmethyl, ethylsulfonylmethyl and propylsulfonylmethyl. Theterm "arylsulfonyl" embraces aryl radicals as defined above, attached toa sulfonyl radical. Examples of such radicals include phenylsulfonyl.The terms "sulfamyl", "aminosulfonyll" and "sulfonamidyl" denotes NH₂ O₂S--. The terms "N-alkylaminosulfonyl" and "N,N-dialkylaminosulfonyl"denote aminosulfonyl radicals substituted, respectively, with one alkylradical, a cycloalkyl ring, or two alkyl radicals. The terms"N-arylaminosulfonyl" and "N-alkyl-N-arylaminosulfonyl" denoteaminosulfonyl radicals substituted with one aryl radical or one alkyland one aryl radical, respectively. The term "acyl" denotes a radicalprovided by the residue after removal of hydroxyl from an organic acid.Examples of such acyl radicals include formyl, alkanoyl and aroylradicals. The terms "carboxy" or "carboxyl", whether used alone or withother terms, such as "carboxyalkyl", denotes --CO₂ H. The term"carbonyl", whether used alone or with other terms, such as"alkoxycarbonyl", denotes --(C═O)--. The term "alkoxycarbonyl" means aradical containing an alkoxy radical, as defined above, attached via anoxygen atom to a carbonyl radical. Preferably, "lower alkoxycarbonyl"embraces alkoxy radicals having one to six carbon atoms. Examples ofsuch "lower alkoxycarbonyl" ester radicals include substituted orunsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,butoxycarbonyl and hexyloxycarbonyl. The term "alkylcarbonyl" includesradicals having alkyl, aryl and aralkyl radicals, respectively, asdefined above, attached via an oxygen atom to a carbonyl radical. Morepreferred alkylcarbonyl radicals are "lower alkylcarbonyl" radicalshaving one to six carbon atoms. Examples of such radicals includemethylcarbonyl and ethylcarbonyl. The term "alkylcarbonylalkyl" embracesradicals having "alkylcarbonyl", as defined above substituted to analkyl radical. More preferred alkylcarbonylalkyl radicals are "loweralkylcarbonylalkyl" having lower alkylcarbonyl radicals as defined aboveattached to one to six carbon atoms. Examples of such loweralkylcarbonylalkyl radicals include methylcarbonylmethyl. The term"alkoxycarbonylalkyl" embraces radicals having "alkoxycarbonyl", asdefined above substituted to an alkyl radical. More preferredalkoxycarbonylalkyl radicals are "lower alkoxycarbonylalkyl" havinglower alkoxycarbonyl radicals as defined above attached to one to sixcarbon atoms. Examples of such lower alkoxycarbonylalkyl radicalsinclude methoxycarbonylmethyl. The term "carboxyalkyll" embracesradicals having a carboxy radical as defined above, attached to an alkylradical. More preferred are "lower carboxyalkyl" having alkyl portionsof one to six carbon atoms. The term "aminoalkyl" embraces alkylradicals substituted with amino radicals. More preferred aminoalkylradicals are "lower aminoalkyl" having one to six carbon atoms. Examplesinclude aminomethyl, aminoethyl and aminobutyl. The term "alkylamino"denotes amino groups which have been substituted with one or two alkylradicals. Preferred alkylamino radicals are "lower alkylamino" havingalkyl portions of one to six carbon atoms. Examples includeN-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino and thelike. The term "alkylaminocarbonyl" embraces alkylamino radicals, asdescribed above, attached to a carbonyl radical. More preferredalkylaminocarbonyl radicals are "lower alkylaminocarbonyl" having loweralkylamino radicals, as described above, attached to a carbonyl radical.Examples of such radicals include N-methylaminocarbonyl andN,N-dimethylcarbonyl. The term "arylaminol" denotes amino groups whichhave been substituted with one or two aryl radicals, such asN-phenylamino. The "arylamino" radicals may be further substituted onthe aryl ring portion of the radical. The term "arylaminocarbonyl"embraces arylamino radicals, as described above, connected to a carbonylradical. An example of such radicals includes phenylaminocarbonyl. Theterm "N-alkyl-N-arylaminocarbonyl" embraces arylamino radicals, asdescribed above, to a carbonyl radical. An example of such radicalsincludes phenylaminocarbonyl. The term "aminocarbonyl" denotes an amidegroup of the formula --C(═O)NH_(b) 2. The term"N-alkyl-N-arylaminocarbonyl" embraces aminocarbonyl radicals, asdescribed above, substituted with one alkyl and one aryl radical. Anexample of such radicals is N-methyl-N-phenylaminocarbonyl. The term"aminocarbonylalkyl" denotes an aminocarbonyl radical attached to analkyl radical, as described above. An example of such radicals isaminocarbonylmethyl. The term "amidino" denotes an --C(═NH)--NH₂radical. The term "cyanoamidino" denotes an --C(═N--CN)--NH₂ radical.The term "cycloalkyl" embraces radicals having three to ten carbonatoms, such as cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl. The term "acylamino" embraces an amino radical substitutedwith an acyl group. An examples of an "acylamino" radical is acetylamino(CH₃ C(═O)--NH--).

The present invention comprises a pharmaceutical composition comprisinga therapeutically-effective amount of a compound of Formula I inassociation with at least one pharmaceutically-acceptable carrier,adjuvant or diluent.

The present invention also comprises a method of treating inflammationor inflammation-associated disorders in a subject, the method comprisingadministering to the subject having such inflammation or disorder atherapeutically-effective amount of a compound of Formula I.

Compounds of Formula I would also be capable of inhibiting cytokines,such as TNF, IL-1, IL-6, and IL-8. As such, the compounds can be used inthe manufacture of a medicament or in a method for the treatment for theprophylactic or therapeutic treatment of diseases mediated by cytokines,such as TNF, IL-1, IL-6, and IL-8.

Also included in the family of compounds of Formula I are thepharmaceutically-acceptable salts thereof. The term"pharmaceutically-acceptable salts" embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, example of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic,p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethylsulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic,cyclohexylaminosulfonic, algenic, β-hydroxybutyric, salicylic,galactaric and galacturonic acid. Suitable pharmaceutically-acceptablebase addition salts of compounds of Formula I include metallic saltsmade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc or organic salts made from N,N'-dibenzylethylenediamine, choline,chloroprocaine, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine. All of these salts may be prepared byconventional means from the corresponding compound of Formula I byreacting, for example, the appropriate acid or base with the compound ofFormula I.

GENERAL SYNTHETIC PROCEDURES

The compounds of the invention can be synthesized according to thefollowing procedures of Schemes I-XII, wherein the R¹ -R⁵ substituentsare as defined for Formulas I-II, above, except where further noted.##STR326##

Synthetic Scheme I illustrates the procedure used to prepare theantiinflammatory pyrazoles 3 of the present invention. 1,3-Dicarbonylcompounds such as 1, or the shown enol form which is in equilibrium tothe diketone, are reacted with a hydrazine hydrochloride 2 in warmethanol to provide the pyrazoles 3 via a condensation reaction.##STR327##

Synthetic Scheme II illustrates the four step procedure for thepreparation of substituted diketones 8. In step one, an appropriatelysubstituted methyl halide 4 (where X is chloro for example) is convertedinto the corresponding thiouronium salt 5 upon treatment with thiourea.In step two, the thioutonium salt 5 is converted according to theprocedure of Lumma and Berchtold (J. Org. Chem., 34, 1566 (1969)) to thefree mercaptide and then trapped with chloroacetic acid or a relatedsalt to provide the acetic acid derivatives 6. In step three, the acids6 are reacted with trifluoroacetic anhydride (TFAA) in trifluoroaceticacid (TFA) to give the ketones 7. In step four, the ketones 7 are firsttreated with base, such as sodium methoxide or lithium diisopropylamide(LDA), followed by condensation with a suitable acylating agent, R¹COLG, (where LG represents an appropriate leaving group such as methoxy,chloro, imidazole and the like) in an appropriate solvent, such asmethanol, diethyl ether or tetrahydrofuran, to provide the desireddiketones 8 which are suitable for conversion into antiinflammatorypyrazoles as illustrated in Scheme I. ##STR328##

Synthetic Scheme III illustrates the four step procedure for thepreparation of substituted isothiochromanone 1,3-carbonyl derivatives13. In step one, an appropriately substituted benzyl alcohol 9 isconverted into the corresponding benzyl chloride by stirring withconcentrated hydrochloric acid and then immediately converted into athiouronium salt 10 upon treatment with thiourea at reflux. In step two,the thiouronium salt is converted to the free mercaptide and thentrapped with chloroacetic acid or a related salt to provide the aceticacid derivatives 11. In step three, the acids 11 are reacted withtrifluoroacetic anhydride (TFAA) in trifluoroacetic acid (TFA) to givethe isothiochromanone products 12. In step four, the isothiochromanones12 are first treated with base, such as sodium methoxide, sodiumbistrimethylsilylamide or lithium diisopropylamide (LDA), followed bycondensation with a suitable acylating agent, R¹ COLG, (where LG isdefined as in Scheme II) in an appropriate solvent, such as methanol,diethyl ether or tetrahydrofuran, to provide 1,3-dicarbonyl compounds 13which are suitable for conversion into antiinflammatory pyrazoles asillustrated in Scheme I.

Alternatively, the dicarbonyl compounds 13 can be directly prepared fromcommercially available isothiochromanones 12. The thiouronium salts 10can be prepared from commercially available benzyl halides. ##STR329##

Synthetic Scheme IV illustrates a three step procedure used for thepreparation of substituted thiochromanone 1,3-dicarbonyl derivatives 17.In step one, an appropriate substituted thiophenol 14 is converted intothe corresponding propionic acid derivatives 15 upon treatment withacrylic acid at a temperature in a range of room temperature to about50° C. In step two, the propionic acids 15 are subjected to treatmentwith a mixture of trifluoroacetic anhydride and trifluoroacetic acid toeffect intramolecular Friedel-Crafts acylation, thus providingthiochromanones 16. In the last step, substituted thiochromanones 16 arefirst treated with a base, such as lithium diisopropyl amide or sodiummethoxide (LDA), followed by condensation with suitable acylating agentsR¹ COLG (as defined in Scheme II) in an appropriate solvent such asdiethylether, methanol or tetrahydrofuran to provide the 1,3-dicarbonylcompounds 17 which are suitable for conversion into antiinflammatorypyrazoles as illustrated in Scheme I.

Alternatively, the dicarbonyl compounds 17 can be directly prepared fromcommercially available thio-4-chromanones 16. ##STR330##

Synthetic Scheme V details the three step procedure used to preparesubstituted 1,3-dicarbonyl chromanone derivatives 21. In step one,substituted phenols 18 are condensed with acrylic acid to afford3-phenoxypropionic acids 19. In step two, the acids 19 are treated witha mixture of trifluoroacetic anhydride and trifluoroacetic acid toaffect intramolecular Friedel-Crafts acylation affording selectedchromanones 20. In step three, substituted chromanones 20 are firsttreated with base, such as lithium diisopropylamide (LDA) or sodiummethoxide followed by condensation with suitable acylating agents, R¹COLG (where LG represents leaving group as previously defined in SchemeII in an appropriate solvent such as diethyl ether or methanol) toprovide 1,3-dicarbonyl compounds 21 which are suitable for conversioninto antiinflammatory pyrazoles as illustrated in Scheme I.

Alternatively, the dicarbonyl compounds 21 can be directly formed fromcommercially available chromanones 20. ##STR331##

Synthetic Scheme VI illustrates a three step procedure used to preparesubstituted 1,3-dicarbonyl isochromanone derivatives 25. In step one,selected benzyl alcohol derivatives 22 are treated with sodium hydrideand subsequently treated with ethyl bromoacetate to provide the desiredethers 23. In step two, the ester group of 23 is hydrolyzed with aqueoussodium hydroxide and then treated with a mixture of trifluoroacetic acidand trifluoroacetic anhydride to promote intramolecular Friedel-Craftsacylation affording isochromanone 24 derivatives. In the third step, theisochromanones 24 are first treated with a base such as lithiumdiisopropylamide (LDA) or sodium methoxide followed by condensation withsuitable acylating agents (R¹ COLG) to provide the 1,3-dicarbonylcompounds 25 which were suitable for conversion into antiinflammatorypyrazoles as illustrated in Scheme I. ##STR332##

Synthetic Scheme VII illustrates a procedure used to prepare themethylsulfonylphenylhydrazine hydrochloride and thesulfonamidylphenylhydrazine hydrochlorides 27 as used in Scheme I. Thesulfonylphenylhydrazine 26 is converted to the hydrochloride salt bystirring with a 4N solution of hydrochloric acid in a solvent such asdioxane. ##STR333##

Synthetic Scheme VIII illustrates a procedure used to preparesubstituted 3-coumaranones 29. Coumaranones 28 are first treated with abase, such as lithium diisopropyl amide or sodium methoxide (LDA)followed by condensation with suitable acylating agents R¹ COLG (asdefined in Scheme II) in an appropriate solvent such as diethylether,methanol or tetrahydrofuran to provide the 1,3-dicarbonyl compounds 29which are suitable for conversion into antiinflammatory pyrazoles asillustrated in Scheme I. ##STR334##

Synthetic Scheme IX illustrates a two step procedure used for thepreparation of substituted benzylalcohols 9. In step one, a mixture ofpotassium tert-butoxide and anhydrous tetrahydrofuran, cooled to -78° C.and treated with a 1.6M solution of n-butyllithium in hexanes, is addedto an appropriate substituted benzene 30 the anion thereby generated isreacted with carbon dioxide to yield the benzoic acid 31. In step two,the benzoic acid 31 is dissolved in a solvent, such as tetrahydrofuran,and treated with a reducing agent, such as borane dimethyl sulfidecomplex, to form the desired benzyl alcohol 9. ##STR335##

Synthetic Scheme X illustrates a procedure used for the preparation ofthe antiinflammatory oxidized thio-containing fused tricyclic pyrazoles33. The appropriate pyrazole 32 from Scheme I, where A is S or--(CH₂)_(m) S(CH₂)_(n) --, is treated with an oxidizing agent such asm-chloroperbenzoic acid (MCPBA) or hydrogen peroxide. Compounds havingdiffering amounts of oxidation (sulfinyls and sulfones) can beseparated, such as by chromatography. ##STR336##

Synthetic Scheme XI shows procedures for preparing antiinflammatoryagents 36, 37 and 38 of Formula I. The esters 35, which can be preparedas shown in Scheme I, is dissolved in aqueous ethanol and a base such as10% NaOH is added. The reaction is heated to reflux to give the acids36. The acids 36 can be converted to the fused pyrazole with a hydridoradical by decarboxylation by heating to about 290° C. to give thedecarboxylated products 37. The acids 36 also can be converted to theappropriate amides 38 by dissolving in methanol and treating with anappropriate amine in the presence of a condensing agent such asdicyclohexylcarbodiimide (DCC). The amides 38 can also be prepared bydirect aminolysis of 35. ##STR337##

Synthetic Scheme XII shows the two step procedure for preparation ofsubstituted heteroarylhydrazine compounds 41 as used in Scheme I whereR² is thienyl. In step 1, the heteroarylsulfonyl chloride 39 (where LGrepresents a leaving group such as halo) is treated with ammonia to givethe heteroaryl sulfonamides 40. In step 2, the heteroaryl sulfonamides40 are treated with hydrazine to give the substitutedheteroarlhydrazines 41.

The following examples contain detailed descriptions of the methods ofpreparation of compounds of Formula I-II. These detailed descriptionsfall within the scope, and serve to exemplify, the above describedGeneral Synthetic Procedures which form part of the invention. Thesedetailed descriptions are presented for illustrative purposes only andare not intended as a restriction on the scope of the invention. Allparts are by weight and temperatures are in Degrees centigrade unlessotherwise indicated. ##STR338## Step 1. Preparation of2-fluoro-3-methoxybenzoic acid.

A mixture of potassium tert-butoxide (30.80 g, 274 mmol) and anhydroustetrahydrofuran (300 mL) was cooled to -78° C. and treated with a 1.6Msolution of n-butyllithium (172 mL, 275 mmol) in hexanes. After stirringfor 15 minutes, 2-fluoroanisole (31.35 g, 248 mmol) was added and thereaction was stirred an additional 1.8 hours. The reaction was pouredinto dry ice and warmed to room temperature. Water (250 mL) was addedand after extracting with ether (160 mL), the aqueous layer wasacidified with concentrated hydrochloric acid, and filtered to give2-fluoro-3-methoxybenzoic acid (21.43 g, 51%) as a yellow solid: mp155°-160° C.; ¹ H NMR (acetone-d₆) 300 MHz 7.46 (ddd, J=6.0 Hz J=1.8 HzJ=1.4 Hz, 1H) 7.36 (dt, J=1.6 Hz J=8.1 Hz, 1H) 7.20 (dt, J=1.4 Hz J=8.1Hz, 1H) 3.92 (s, 3H); ¹⁹ F NMR (acetone-d₆) 300 MHz -134.04 (m). Massspectrum: M+H=171.

Step 2. Preparation of 2-fluoro-3-methoxybenzyl alcohol.

2-Fluoro-3-methoxybenzoic acid from Step 1 (16.65 g, 98 mmol) wasdissolved in anhydrous tetrahydrofuran (60 mL), cooled in an ice bath,and treated with borane dimethyl sulfide complex (19 mL, 190 mmol). Thereaction was stirred at room temperature for 4.2 hours, quenched by theslow addition of methanol, and concentrated in vacuo. The residue wasdissolved in ethyl acetate, treated with 3N hydrochloric acid andfiltered through diatomaceous earth. The organic layer of the filtratewas collected, washed with NaHCO₃, brine, dried over MgSO₄ andreconcentrated in vacuo to give 2-fluoro-3-methoxybenzyl alcohol (12.35g, 81%) as a white solid: mp 53°-57° C.; ¹ H NMR (acetone-d₆) 300 MHz7.07 (m, 3H) 4.67 (d, J=5.8 Hz, 2H) 4.24 (t, J=5.8 Hz, 1H) 3.86 (s, 3H);¹⁹ F NMR (acetone-d₆) 300 MHz -144.77(m).

Step 3. Preparation of 2-fluoro-3-methoxybenzyl chloride.

2-Fluoro-3-methoxybenzyl alcohol from Step 2 (12.16 g, 78 mmol) wasdissolved in concentrated hydrochloric acid (60 mL) and hydrochloricacid gas was bubbled through the solution for 3 minutes. The reactionwas stirred at room temperature (21 hours). The reaction mixture wasextracted with ether, dried over MgSO₄ and concentrated in vacuo to give2-fluoro-3-methoxybenzyl chloride (10.36 g, 76%) as a green oil: ¹ H NNR(acetone-d₆) 300 MHz 7.12 (m, 2H) 7.05 (m, 1H) 4.73 (s, 2H) 3.89 (s,3H); ¹⁹ F NMR (acetone-d6) 300 MHz -142.07(m).

Step 4. Preparation of S-(2-fluoro-3-methoxybenzyl)-isothiouroniumchloride.

Thiourea (4.47 g, 59 mmol) was added to a solution of2-fluoro-3-methoxybenzyl chloride from Step 3 (10.20 g, 58 mmol) inmethanol (25 mL). The reaction was heated to reflux for 3.3 hours,concentrated in vacuo, triturated with ether, and filtered to give awhite solid (14.65 g, 100%).

Step 5. Preparation of 3-(2-fluoro-3-methoxyphenylthio)propanoic acid.

The thiouronium salt from Step 4 (14.65 g, 58 mmol) was added to sodiumchloroacetate (10.44 g, 90 mmol), ethanol (60 mL) and water (25 mL).After heating to reflux, a solution of NaOH (10.66 g, 266 mmol) in water(35 mL) was added to the reaction dropwise. After stirring for 16.6hours, the reaction was acidified with concentrated hydrochloric acid,extracted with ether, washed with brine, dried over MgSO₄, concentratedin vacuo and recrystallized from ether/hexane to give a brown solid(7.70 g, 57%): mp 72°-74° C.; ¹ H NMR (CDCl₃) 300 MHz 7.03 (m, 1H) 6.91(m, 2H) 3.89 (d, J=1.0 Hz, 2H) 3.88 (s, 3H) 3.19 (s, 2H); ¹⁹ F NMR(CDCl₃) 300 MHz -140.76(m).

Step 6. Preparation of 8-fluoro-7-methoxyisothiochroman-4-one.

The acid from Step 5 (7.63 g, 33 mmol) was dissolved in trifluoroaceticacid (12 mL), treated with trifluoroacetic anhydride (4 mL) and stirredat room temperature (8 minutes). The reaction was poured into 10% Na₂CO₃ (50 mL) and extracted with ethyl acetate, washed with brine, driedover MgSO₄ and concentrated in vacuo to give8-fluoro-7-methoxyisothiochroman-4-one (5.42 g, 77%) as a brown solid:mp 85°-92° C.; ¹ H NMR (CDCl₃) 300 MHz 7.83 (d, J=8.9 Hz, 1H) 7.19 (t,J=8.5 Hz, 1H) 4.01 (s, 2H) 3.98 (s, 3H) 3.55 (s, 2H); ¹⁹ F NMR (CDCl₃)300 MHz -141.24(m).

Step 7. Preparation of6-fluoro-7-methoxy-3-(trifluoroacetyl)isothiochroman-4-one.

8-Fluoro-7-methoxyisothiochroman-4-one from Step 6 (1.70 g, 8.0 mmol)was dissolved in anhydrous tetrahydrofuran (30 mL), cooled to -78° C.,and treated with a 1.0M tetrahydrofuran solution of sodiumbistrimethylsilyl amide (10 mL, 10 mmol). After 30 minutes,N-trifluoroacetylimidazole (1.85 g in 10.0 mL THF, 11.3 mmol) was addedand the reaction was stirred and warmed to room temperature overnight(19.4 hours). The reaction was treated with 1N hydrochloric acid (30mL). The organic layer was collected, washed with brine, dried overMgSO₄, concentrated in vacuo and recrystallized fromdichloromethane/isooctane to give the diketone (1.14 g, 46%) as a brownsolid: mp 162°-164° C.; ¹ H NMR (CDCl₃) 300 MHz 15.50 (s, 1H) 7.82 (dd,J=8.9 Hz J=1.0 Hz, 1H) 6.99 (t, J=8.5 Hz, 1H) 3.99 (s, 3H) 3.89 (s, 2H)2.43 (s, 2H); ¹⁹ F NMR (CDCl₃) 300 MHz: -72.46 (s) -140.30 (d). Massspectrum: M+H=309.

Step 8. Preparation of 4-6-fluoro-1,5-dihydro-7-methoxy-3-(trifluoromethyl)- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide.

4-Sulfonamidophenylhydrazine hydrochloride (0.77 g, 3.4 mmol) was addedto a stirred solution of the diketone from Step 7 (0.93 g, 3.0 mmol) inethanol (10 mL). The reaction was heated to reflux and stirred for 20.4hours. The reaction mixture was filtered while hot to give the pyrazoleas gray needles (0.55 g, 40%): mp 250°-252° C.; ¹ H NMR (acetone-d₆) 300MHz 8.08 (d, J=8.9 Hz, 2H) 7.85 (d, J=8.7 Hz, 2H) 7.01 (t, J=8.7 Hz, 1H)6.81 (br s, 2H) 6.72 (dd, J=8.6 Hz J=1.9 Hz, 1H) 4.20 (s, 2H) 3.91 (s,3H); ¹⁹ F NMR (acetone-d₆) 300 MHz -63.32 (s) -140.16 (d).

EXAMPLE 2 ##STR339##

4-(Methylsulfonyl)phenylhydrazine (0.75 g, 4.0 mmol) was converted tothe hydrochloride salt by stirring with a 4N solution of hydrochloricacid in dioxane (10 mL) for 30 minutes. The dioxane was removed in vacuoand the 4-(methylsulfonyl)phenyl hydrazine hydrochloride was combinedwith the diketone from Example 1, Step 7 (0.89 g, 2.9 mmol) and ethanol(15 mL), heated to reflux and stirred for 14.5 hours. The reactionmixture was filtered while hot and the filtrate was concentrated invacuo. The residue was dissolved in ethyl acetate, washed with water andwith brine, dried over MgSO₄, reconcentrated in vacuo and passed througha column of silica gel, eluting with 20% ethyl acetate/hexane to givethe pyrazole (0.46 g, 35%) as a yellow solid: mp 213°-215° C.; ¹ H NMR(acetone-d₆) 300 MHz 8.15 (d, J=8.7 Hz, 2H) 7.94 (d, J=8.7 Hz, 2H) 7.01(t, J=8.7 Hz, 1H) 6.73 (d, J=8.7 Hz, 1H) 4.21 (s, 2H) 3.90 (s, 3H) 3.23(s, 3H); ¹⁹ F NMR (acetone-d₆) 300 MHz -63.41 (s) -140.17 (d). Massspectrum: M+=458.1.

EXAMPLE 3 ##STR340## Step 1. Preparation of3-(trifluoroacetyl)-4-chromanone.

Ethyl trifluoroacetate (9.78 g, 68 mmol) was dissolved in ether (50 mL).To the stirred solution was added 25% sodium methoxide (15.11 g, 70mmol), followed by 4-chromanone (10.07 g, 68 mmol) dissolved in ether(25 mL). The reaction was stirred at room temperature overnight (18.3hours), poured into a separatory funnel and washed with 3N hydrochloricacid (20 mL) and with brine (20 mL), dried over MgSO₄, concentrated invacuo, and recrystallized from ether/hexane to give a yellow solid(10.72 g, 65%): mp 81°-83° C.; ¹ H NMR (CDCl₃) 300 MHz 16.04 (br s, 1H)7.84 (d, J=7.9 Hz, 1H) 7.51 (m, 1H) 7.09 (m, 1H) 6.98 (d, J=8.5 Hz, 1H)5.08 (s, 2H); ¹⁹ F NMR (CDCl₃) 300 MHz: -72.56 (s). Mass spectrum:M+=244.

Step 2. Preparation of 4- 1,4-dihydro-3-(trifluoromethyl)- 1!benzopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide.

4-Sulfonamidophenylhydrazine hydrochloride (4.57 g, 20.4 mmol) was addedto a stirred solution of the diketone from Step 1 (4.59 g, 18.8 mmol) inethanol (80 mL). The reaction was heated to reflux and stirred overnight(17.3 hours). The reaction mixture was filtered while hot to give thepyrazole as a white solid (3.99 g, 54%). Upon cooling, the filtrateyielded an additional 1.97 g (26%): mp 250°-251° C.; ¹ H NMR(acetone-d₆) 300 MHz 8.14 (d, J=8.7 Hz, 2H), 7.87 (d, J=8.7 Hz, 2H) 7.30(m, 1H), 7.08 (d, J=8.1 Hz, 1H) 6.89 (m, 3H) 5.41 (s, 2H); ¹⁹ F NMR(acetone-d₆) 300 MHz -62.42 (s). High resolution mass spectrum Calc'd.for C₁₇ H₁₂ F₃ N₃ O₃ S: 395.0551. Found: 395.0551.

EXAMPLE 4 ##STR341## Step 1. Preparation ofmethyl-3-(1-oxo-2-carboxy)-4-chromanone.

4-Chromanone (9.72 g, 65.6 mmol) was added to dimethyl oxalate (8.92 g,75.5 mmol) and methanol (75 mL). The solution was treated with sodiummethoxide (25%) in methanol (18.52 g, 85.7 mmol) and stirred at roomtemperature for 18.8 hours. The reaction was treated with 3Nhydrochloric acid (30 mL), filtered, and recrystallized from ethylacetate/isooctane to give the diketone (11.31 g, 74%) as a yellow solid:mp 85°-87° C.; ¹ H NMR (acetone-d₆) 300 MHz 7.87 (d, J=7.9 Hz, 1H) 7.61(m, 1H) 7.14 (m, 1H) 7.02 (d, J=8.3 Hz, 1H) 5.35 (s, 2H) 3.92 (s, 3H).Mass spectrum: M+Li=234.

Step 2. Preparation of methyl 1- 4-(aminosulfonyl)phenyl!-1,4-dihydro-1!benzopyrano 4,3-c!pyrazol-3-yl!carboxylate.

4-Sulfonamidophenylhydrazine hydrochloride (6.52 g, 29.1 mmol) was addedto a stirred solution of the diketone from Step 1 (6.23 g, 26.6 mmol) inmethanol (MeOH) (150 mL). The reaction was heated to reflux and stirredfor 15.1 hours. The reaction mixture was filtered, washed with MeOH anddried under vacuum to give the pyrazole as a pale green solid (9.81 g,96%): mp >304° C.; ¹ H NMR (DMSO-d₆) 300 MHz 8.02 (d, J=8.7 Hz, 2H) 7.83(d, J=8.5 Hz, 2H) 7.60 (br s, 2H) 7.25 (2d, 1H) 7.06 (d, J=7.5 Hz,1H)6.84 (2d, 1H) 6.71 (d, J=7.9 Hz, 1H) 5.46 (s, 2H) 3.85 (s, 3H). Massspectrum: M+H=386.

EXAMPLE 5 ##STR342## Step 1. Preparation of6-fluoro-3-(trifluoroacetyl)-4-chromanone.

Ethyl trifluoroacetate (4.33 g, 30 mmol) was dissolved in ether (25 mL)and treated with sodium methoxide (25%, 7.08 g, 33 mmol). To the stirredsolution was added 6-fluoro-4-chromanone (4.92 g, 30 mmol) andadditional ether (10 mL). The reaction was stirred at room temperatureovernight (19.0 hours) and treated with 3N hydrochloric acid (15 mL).The organic layer was collected, washed with brine, dried over MgSO₄,concentrated in vacuo and recrystallized from ether/hexane to give ayellow solid (3.98 g, 51%): mp 107°-112° C.; ¹ H NMR (CDCl₃) 300 MHz14.95 (s, 1H) 7.52 (dd, 1H) 7.23 (m, 1H) 6.97 (m, 1H) 5.07 (s, 2H); ¹⁹ FNMR (CDCl₃) 300 MHz -72.60 (s), -119.93 (m). Mass spectrum: M+=262.

Step 2. Preparation of 4- 1,4-dihydro-8-fluoro-3-(trifluoromethyl)-1!benzopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

4-Sulfonamidophenylhydrazine hydrochloride (1.54 g, 6.9 mmol) was addedto a stirred solution of the diketone from Step 1 (1.62 g, 6.2 mmol) inethanol (35 mL). The reaction was heated to reflux and stirred overnight(17.3 hours). The reaction mixture was filtered while hot to give thepyrazole as a white solid (1.09 g, 43%). Upon cooling, the filtrateyielded an additional 0.70 g (27%): mp 251°-251.5° C.; ¹ H NMR(acetone-d₆) 300 MHz 8.17 (d, J=8.5 Hz, 2H) 7.91 (d, J=8.7 Hz, 2H) 7.11(m, 2H) 6.87 (br s, 1H) 6.58 (dd, J=2.4 Hz, 9.5 Hz, 3H) 5.41 (s, 2H); ¹⁹F NMR (acetone-d₆) 300 MHz -62.46 (s). High resolution mass spectrumCalc'd. for C₁₇ H₁₁ F₄ N₃ O₃ S: 413.0457. Found: 413.0462.

EXAMPLE 6 ##STR343## Step 1. Preparation of2-(trifluoroacetyl)-3-coumaranone.

Ethyl trifluoroacetate (1.90 g, 14 mmol) was dissolved in ether (15 mL)and treated with sodium methoxide (25%) (3.67 g, 17 mmol). To thestirred solution was added 3-coumaranone (1.50 g, 11 mmol). The reactionwas stirred at room temperature overnight (19 hours) and treated with 3NHCl (8 mL). The organic layer was collected, washed with brine, driedover MgSO₄, and concentrated in vacuo to give a reddish brown solid(2.19 g, 85%): mp 108°-111° C.; ¹ H NMR (CDCl₃) 300 MHz 7.84 (d, J=8.1Hz, 1H) 7.66 (m, 1H) 7.52 (d, J=8.7 Hz, 1H) 7.37 (m, 1H). Mass spectrum:M+H=231.

Step 2. Preparation of 4- 3-(trifluoromethyl)-1H-benzofuro3,2-c!pyrazol-1-yl!benzenesulfonamide.

4-Sulfonamidophenylhydrazine hydrochloride (1.15 g, 5.0 mmol) was addedto a stirred solution of the diketone from Step 1 (1.13 g, 4.9 mmol) inethanol (10 mL). The reaction was heated to reflux and stirred for 2.5hours. The reaction mixture was filtered to give the pyrazole as a brownsolid (1.07 g, 57%): mp 190°-195° C.; ¹ H NMR (acetone-d₆) 300 MHz7.82-7.90 (m, 3H) 7.34-7.53 (m, 5H); ¹⁹ F NMR (acetone-d₆) 300 MHz-65.47 (s).

EXAMPLE 7 ##STR344## Step 1. Preparation of3-(trifluoroacetyl)thio-4-chromanone.

Ethyl trifluoroacetate (8.78 g, 62 mmol) was dissolved in ether (50 mL).To the stirred solution was added sodium methoxide (14.35 g, 66 mmol)followed by thio-4-chromanone (9.43 g, 57 mmol) dissolved in ether (10mL). The reaction was stirred at room temperature overnight (17.8 hrs)and treated with 3N HCl (25 mL). The organic layer was collected, washedwith brine, dried over MgSO₄, concentrated in vacuo and recrystallizedfrom ether/hexane to give a yellow solid (10.20 g, 68%): mp 75°-79° C.;¹ H NMR (CDCl₃) 300 MHz 15.62 (s, 1H) 7.99 (d, J=7.9Hz, 1H) 7.24-7.42(m, 3H) 3.81 (s, 2H); ¹⁹ F NMR (CDCl₃) 300 MHz -71.92 (s). Massspectrum: M+=260.

Step 2. Preparation of 4- 1,4-dihydro-3-(trifluoromethyl)-1!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

4-Sulfonamidophenylhydrazine hydrochloride (5.74 g, 25.6 mmol) was addedto a stirred solution of the diketone from Step 1 (6.04 g, 23.2 mmol) inethanol (95 mL). The reaction was heated to reflux and stirred overnight(17.0 hours). The reaction mixture was filtered, and the filtrate cooledto 0° C. and filtered to give the pyrazole as a yellow solid (4.42 g,46%): mp 213°-215° C.; ¹ H NMR (acetone-d₆) 300 MHz 8.09 (d, J=8.9 Hz,2H) 7.75 (d, J=8.7 Hz, 2H) 7.53 (d, J=7.8 Hz, 1H) 7.29 (2d, 1H) 7.07(2d, 1H) 6.94 (d, J=8.1 Hz, 2H) 6.92 (br s, 1H) 4.09 (s, 2H); ¹⁹ F NMR(acetone-d₆) 300 MHz -62.22 (s). High resolution mass spectrum Calc'd.for C₁₇ H₁₂ F₃ N₃ O₂ S₂ : 411.0323. Found: 411.0330.

EXAMPLE 8 ##STR345## Step 1. Preparation ofmethyl-3-(1-oxo-2-carboxy)thiochroman-4-one.

Thiochroman-4-one (9.84 g, 59.9 mmol) was added to dimethyl oxalate(8.54 g, 72.3 mmol) and methanol (75 mL). The reaction was treated withsodium methoxide (25% in methanol, 15.61 g, 72.2 mmol) and stirred atroom temperature for 17.8 hours. The reaction was treated with 3Nhydrochloric acid (30 mL) and filtered to give the diketone (13.58 g,90%) as an orange solid: mp 94°-97° C.; ¹ H NMR (CDCl₃) 300 MHz 15.94(s, 1H) 8.01 (d, J=7.9 Hz, 1H) 7.24-7.39 (m, 3H) 4.11 (s, 2H) 3.94 (s,3H). Mass spectrum: M+=250.

Step 2. Preparation of methyl 1- 4-(aminosulfonyl)phenyl!-1,4-dihydro-1!benzothiopyrano 4,3-c!pyrazol-3-yl!carboxylate.

4-Sulfonamidophenylhydrazine hydrochloride (12.06 g, 53.9 mmol) wasadded to a stirred solution of the diketone from Step 1 (12.23 g, 48.9mmol) in MeOH (250 mL). The reaction was heated to reflux and stirredfor 6.5 hours. The reaction mixture was filtered, washed with MeOH anddried under vacuum to give the pyrazole as an orange solid (17.88 g,91%): mp 265°-269° C.; ¹ H NMR (DMSO-d₆) 300 MHz 7.97 (d, J=8.5 Hz, 2H)7.69 (d, J=8.5 Hz, 2H) 7.58 (br s, 2H) 7.50 (d, J=7.9 Hz, 1H) 7.24 (t,J=7.7 Hz, 1H) 7.04 (d, J=7.7 Hz, 1H) 6.76 (d, J=7.9 Hz, 1H) 4.21 (s, 2H)3.86 (s, 3H). Mass spectrum: M+H=402.

EXAMPLE 9 ##STR346## Step 1. Preparation of3-(2,3-dichlorophenylthio)propanoic acid.

2,3-Dichiorothiophenol (4.94 g, 28 mmol) was added to acrylic acid (2.11g, 29 mmol) and stirred at 50° C. for 3 hours. The reaction mixture waspoured into 10% Na₂ CO₃ and extracted with ether. The aqueous layer wasacidified with concentrated hydrochloric acid, extracted with ether,washed with brine, dried over MgSO₄, and concentrated in vacuo to givethe 3-(2,3-dichlorophenylthio)propanoic acid (3.88 g), contaminated withsome acrylic acid, as a clear oil which was used without furtherpurification in the next step.

Step 2. Preparation of 7,8-dichlorothiochroman-4-one.

The 3-(2,3-dichlorophenylthio)propanoic acid from Step 1 (3.88 g, 15mmol) was dissolved in trifluoroacetic acid (10 mL), treated withtrifluoroacetic anhydride (5 mL) and stirred at room temperature for68.2 hours. The reaction mixture was poured into 10% Na₂ CO₃ (100 mL),extracted with ethyl acetate, washed with brine, dried over MgSO₄, andconcentrated in vacuo to give a yellow oil. The crude material waspassed through a column of silica gel eluting with 40% ethylacetate/hexane to give 7,8-dichlorothiochroman-4-one as a white solid(0.46 g, 13%): mp 93°-102° C.; ¹ H NMR (CDCl₃) 300 MHz 7.99 (d, J=8.7Hz, 1H) 7.27 (d, J=8.7 Hz, 1H) 3.25 (m, 2H) 2.97 (m, 2H). Mass spectrum:M+=233.

Step 3. Preparation of7,8-dichloro-3-(trifluoroacetyl)thiochroman-4-one.

Ethyl trifluoroacetate (0.29 g, 2.0 mmol) was dissolved in ether (12mL). To the stirred solution was added sodium methoxide (25%) (0.84 g,3.9 mmol), followed by 7,8-dichlorothiochroman-4-one from Step 2 (0.42g, 1.8 mmol). The reaction was stirred at room temperature overnight(19.4 hours) and treated with 3N hydrochloric acid. The organic layerwas collected, washed with brine, dried over MgSO₄, and concentrated invacuo to give a brown oily solid which was used without purification inthe next step.

Step 4. Preparation of 4- 6,7-dichloro-1,4-dihydro-3-(trifluoromethyl)-1!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

4-Sulfonamidophenylhydrazine hydrochloride (0.32 g, 1.4 mmol) was addedto a stirred solution of the diketone from Step 3 (0.44 g, 1.3 mmol) inethanol (10 mL). The reaction was heated to reflux and stirred overnight(19.4 hours). The reaction mixture was filtered and the filtrateconcentrated in vacuo, dissolved in ethyl acetate, washed with water andbrine, dried over MgSO₄, reconcentrated in vacuo, and passed through acolumn of silica gel (hexane/ethyl acetate) to give the pyrazole as awhite solid (0.24 g, 38%): ¹ H NMR (acetone-d₆) 300 MHz 8.08 (d, J=8.7Hz, 2H) 7.77 (d, J=8.7 Hz, 2H) 7.27 (d, J=8.5Hz, 1H) 6.95 (d, J=8.5 Hz,1H) 6.79 (br s, 2H) 4.23 (s, 2H); ¹⁹ F NMR (acetone-d₆) 300 MHz -62.25(s). High resolution mass spectrum Calc'd. for C₁₇ H₁₀ Cl₂ F₃ N₃ O₂ S₂ :479.9622. Found: 479.9565.

EXAMPLE 10 ##STR347## Step 1. Preparation of3-(3-fluorophenylthio)propanoic acid.

3-Fluorothiophenol (5.39 g, 42 mmol) was added to acrylic acid (3.73 g,52 mmol) and stirred at room temperature for 20.2 hours. The reactionmixture solidified, was dissolved in ether and extracted with 10% Na₂CO₃. The aqueous layer was acidified with concentrated hydrochloricacid, extracted with ether, washed with brine, dried over MgSO₄, andconcentrated in vacuo to give the 3-(3-fluorophenylthio)propanoic acid(6.75 g), contaminated with some acrylic acid, as a white solid whichwas used without further purification in the next step.

Step 2. Preparation of 7-fluorothiochroman-4-one.

The acid from Step 1 (6.75 g, 34 mmol) was dissolved in trifluoroaceticacid (20 mL), treated with trifluoroacetic anhydride (10 mL) and stirredat room temperature for 2.2 hours. The reaction mixture was poured into10% Na₂ CO₃ (100 mL), extracted with ether, washed with brine, driedover MgSO₄, and concentrated in vacuo to give a yellow oil which waspassed through a column of silica gel with 20% ethyl acetate/hexane togive 7-fluorothiochroman-4-one as a white solid (2.09 g, 34%): mp61°-66° C.; ¹ H NMR (CDCl₃) 300 MHz 8.13 (m, 1H) 6.98 (m, 1H) 6.86 (m,1H) 3.23 (m, 2H) 2.99 (m, 2H); ¹⁹ F NMR (CDCl₃) 300 MHz -104.70 (m).Mass spectrum: M+H=183.

Step 3. Preparation of 7-fluoro-3-(trifluoroacetyl)thiochroman-4-one.

Ethyl trifluoroacetate (1.04 g, 7.3 mmol) was added to solution of7-fluorothiochroman-4-one from Step 2 (1.24 g, 6.8 mmol) in ether (15mL). The reaction was treated with 25% sodium methoxide (1.86 g, 8.6mmol) and stirred at room temperature for 20.9 hours, then treated with3N hydrochloric acid (10 mL). The organic layer was collected, washedwith brine, dried over MgSO₄, concentrated in vacuo, and recrystallizedfrom dichloromethane/isooctane to give the diketone as a yellow solid(0.58g, 31%): mp 84°-89° C.; ¹ H NMR (CDCl₃) 300 MHz 15.65 (s, 1H) 8.03(m, 1H) 7.08 (m, 1H) 6.97 (m, 1H) 3.83 (s, 2H); ¹⁹ F NMR (CDCl₃) 300 MHz-71.81 (s) -103.04 (m).

Step 4. Preparation of 4- 1,4-dihydro-7-fluoro-3-(trifluoromethyl)-1!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

4-Sulfonamidophenylhydrazine hydrochloride (1.36 g, 6.1 mmol) was addedto a stirred solution of the diketone from Step 3 (1.65 g, 5.9 mmol) inethanol (10 mL). The reaction was heated to reflux and stirred overnight(15.2 hours). The reaction mixture was filtered and the filtrate cooledin ice to give the pyrazole as a white solid (0.24 g, 38%): ¹ H NMR(acetone-d₆) 300 MHz 8.09 (d, J=8.7 Hz, 2H) 7.76 (d, J=8.7 Hz, 2H) 7.38(d, J=9.1 Hz, 1H) 6.99 (m, 1H) 6.88 (m, 1H) 6.80 (br s, 2H) 4.14 (s,2H); ¹⁹ F NMR (acetone-d₆) 300 MHz: -62.25 (s) -112.68 (m). Highresolution mass spectrum Calc'd. for C₁₇ H₁₁ F₄ N₃ O₂ S₂ : 429.0229.Found: 429.0205.

EXAMPLE 11 ##STR348## Step 1. Preparation of3-(2-isopropylphenylthio)propanoic acid.

2-Isopropylthiophenol (4.77 g, 31 mmol) was placed in a flask withacrylic acid (2.37 g, 33 mmol) and stirred at room temperature for 71.8hours. The reaction mixture solidified, was dissolved in ethyl acetateand extracted with 5% NaOH. The aqueous layer was acidified withconcentrated hydrochloric acid, extracted with ethyl acetate, dried overMgSO₄, and concentrated in vacuo to give3-(2-isopropylphenylthio)propanoic acid (6.85 g), contaminated with someacrylic acid, as a yellow solid which was used without furtherpurification in the next step.

Step 2. Preparation of 8-isopropylthiochroman-4-one.

3-(2-Isopropylphenylthio)propanoic acid from Step 1 (6.85 g, 30 mmol)was dissolved in trifluoroacetic acid (20 mL), treated withtrifluoroacetic anhydride (12 mL) and stirred at room temperature (64.2hours). The reaction was concentrated in vacua, and the residuedissolved in ethyl acetate, extracted with 5% NaOH, washed with brine,dried over MgSO₄, and concentrated in vacua to give a brown oil whichwas passed through a column of silica gel eluted with 12% ether/hexaneto give 8-isopropylthiochroman-4-one as a brown oil (1.05 g, 17%): ¹ HNMR (CDCl₃) 300 MHz 8.01 (d, J=7.0 Hz, 1H) 7.38 (d, J=7.5 Hz, 1H) 7.17(t, J=7.8 Hz, 1H) 3.19 (m, 3H) 2.96 (m, 2H) 1.25 (d, J=7.0 Hz 6H).

Step 3. Preparation of 8-isopropyl-3-(trifluoroacetyl)thiochroman-4-one.

Ethyl trifluoroacetate (0.69 g, 4.9 mmol) was added to a solution of2-isopropylthiochroman-4-one from Step 2 (0.97 g, 4.7 mmol) in ether (10mL). The reaction was treated with 25% sodium methoxide (1.08 g, 5.0mmol), stirred at room temperature for 18.2 hours and treated with 3Nhydrochloric acid (5 mL). The organic layer was collected, washed withbrine, dried over MgSO₄ and concentrated in vacua to give the diketoneas a brown oil (0.80 g) which was used without further purification inthe next step.

Step 4. Preparation of 4- 1.4-dihydro-6-isopropyl-3-(trifluoromethyl)-1!benzothiopyrano 4 3-c!pyrazol-1-yl!benzenesulfonamide.

4-Sulfonamidophenylhydrazine hydrochloride (0.69 g, 3.1 mmol) was addedto a stirred solution of the diketone from Step 3 (0.83 g, 2.7 mmol) inethanol (10 mL). The reaction was heated to reflux, stirred overnight(16.1 hours) and concentrated in vacuo. The residue was dissolved inethyl acetate washed with water, washed with brine, dried over MgSO₄,reconcentrated in vacuo and passed through a column of silica gel with20% ethyl acetate/hexane to give the pyrazole as a brown solid (0.43 g,35%): mp 183°-186° C.; ¹ H NMR (acetone-d₆) 300 MHz 8.10 (d, J=8.7 Hz,2H) 7.71 (d, J=8.5 Hz, 2H) 7.35 (d, J=7.9 Hz, 1H) 7.04 (t, J=7.9 Hz, 1H)6.79 (m, 3H) 4.04 (s, 2H) 3.46 (m, 1H) 1.28 (d, J=6.8 Hz, 6H); ¹⁹ F NMR(acetone-d₆) 300 MHz -62.19 (s) -112.68 (m). High resolution massspectrum Calc'd. for C₂₀ H₁₈ F₃ N₃ O₂ S₂ : 453.0793. Found: 453.0848.

EXAMPLE 12 ##STR349## Step 1. Preparation of3-(3,4-dimethoxyphenylthio)propanoic acid.

3,4-Dimethoxythiophenol (5.00 g, 29 mmol) was placed in a flask withacrylic acid (2.27 g, 32 mmol) and stirred at room temperature for 22.4hours. The reaction mixture solidified, was dissolved in ethyl acetateand extracted with 10% Na₂ CO₃. The aqueous layer was acidified withconcentrated hydrochloric acid, extracted with ether, dried over MgSO₄,and concentrated in vacuo to give 3-(3,4-dimethoxyphenylthio)propanoicacid (5.39 g , 76%), contaminated with some acrylic acid, as a whitesolid which was used without further purification in the next step: mp62°-64° C.; ¹ H NMR (CDCl₃) 300 MHz 9.80 (br s, 1H) 7.01 (d, J=8.3 Hz,1H) 6.98 (s, 1H) 6.82 (d, J=8.3 Hz, 1H) 3.87 (s, 3H) 3.86 (s, 3H) 3.06(t, J=7.3 Hz, 2H) 2.63 (t, J=7.3 Hz, 2H). Mass spectrum: M+=242.

Step 2. Preparation of 6,7-dimethoxythiochroman-4-one.

The acid from Step 1 (5.23 g, 22 mmol) was dissolved in trifluoroaceticacid (20 mL), treated with trifluoroacetic anhydride (12 mL) and stirredat room temperature (10 minutes). The reaction was poured into 10% Na₂CO₃ (100 mL) and filtered to collect 6,7-dimethoxythiochromanone as ayellow solid (1.12 g, 23%). The filtrate was washed with brine, driedover MgSO₄, concentrated in vacuo and recrystallized from ethylacetate/hexane to give more 6,7-dimethoxythiochromanone (1.77 g, 37%) asan orange solid: mp 138°-143° C.; ¹ H NMR (CDCl₃) 300 MHz 7.60 (s, 1H)6.68 (s, 1H) 3.91 (s, 3H) 3.89 (s, 3H) 3.19 (m, 2H) 2.93 (m, 3H). Massspectrum: M+=224.

Step 3. Preparation of 6,7-dimethoxy-3-trifluoroacetylthiochroman-4-one.

Ethyl trifluoroacetate (0.84 g, 5.9 mmol) was dissolved intetrahydrofuran (20 mL), and treated with 25% sodium methoxide (1.68 g,7.8 mmol). To the stirred solution was added6,7-dimethoxythiochroman-4-one from Step 2 (1.12 g, 5.0 mmol). Thereaction was stirred at room temperature for 87.5 hours, treated with 3NHCl (25 mL) and filtered to give an orange solid (1.04 g, 65%): mp148°-151° C.; ¹ H NMR (CDCl₃) 300 MHz 16.05 (s, 1H), 7.48 (s, 1H) 6.78(s, 1H) 3.94 (s, 3H) 3.92 (s, 3H) 3.83 (s, 2H); ¹⁹ F NMR (CDCl₃) 300 MHz-71.06 (s). Mass spectrum: M+H=321.

Step 4. Preparation of 4- 1,4-dihydro-7,8-dimethoxy-3-(trifluoromethyl)-1!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

4-Sulfonamidophenylhydrazine hydrochloride (0.76 g, 3.4 mmol) was addedto a stirred solution of the diketone from Step 3 (1.00 g, 3.1 mmol) inethanol (20 mL). The reaction was heated to reflux and stirred overnight(15.5 hours). The reaction mixture was filtered and the filtrateconcentrated in vacuo, dissolved in ethyl acetate, washed with water andbrine, dried over MgSO₄, reconcentrated in vacuo, and recrystallizedfrom ethyl acetate/isooctane to give the pyrazole as a yellow solid(0.72 g, 49%): mp 164°-168° C.; ¹ H NMR (acetone-d₆) 300 MHz 8.13 (d,J=8.7 Hz, 2H) 7.77 (d, J=8.5 Hz, 2H) 7.06 (s, 1H) 6.82 (br s, 2H) 6.36(s, 1H) 4.04 (s, 2H) 3.85 (s, 3H) 3.85 (s, 3H); ¹⁹ F NMR (acetone-d₆)300 MHz -62.20(s). High resolution mass spectrum Calc'd. for C₁₉ H₁₆ F₃N₃ O₄ S₂ : 471.0534. Found: 471.0534.

EXAMPLE 13 ##STR350## Step 1. Preparation of3-(3-methoxyphenylthio)propanoic acid.

3-Methoxythiophenol (5.70 g, 41 mmol) was placed in a flask with acrylicacid (2.36 g, 33 mmol) and stirred at room temperature for 113.8 hours.The reaction mixture was dissolved in ether and extracted with 10% Na₂CO₃. The aqueous layer was acidified with concentrated HCl, extractedwith ether, dried over MgSO₄, and concentrated in vacuo to give the3-(3-methoxyphenylthio)propanoic acid (2.55 g, 37%) as a white solid: mp39°-42° C.; ¹ H NMR (CDCl₃) 300 MHz 7.21 (m, 1H) 6.91 (m, 2H) 6.77 (d,J=8.3 Hz, 1H) 3.79 (s, 3H) 3.16 (t, J=7.5 Hz, 2H) 2.68 (t, J=7.3 Hz,2H).

Step 2. Preparation of 7-methoxythiochroman-4-one.

The acid from Step 1 (2.55 g, 12 mmol) was dissolved in trifluoroaceticacid (10 mL), treated with trifluoroacetic anhydride (5 mL) and stirredat room temperature (10 minutes). The reaction was poured into 10% Na₂CO₃ (60 mL), extracted with ether, washed with brine, dried over MgSO₄,and concentrated in vacuo to give a red oil which was passed through acolumn of silica gel with 50% ether/hexane to give7-methoxythiochroman-4-one as an orange solid (1.18 g, 51%): mp 49°-51°C.; ¹ H NMR (CDCl₃) 300 MHz 8.06 (d, J=8.9 Hz, 1H) 6.72 (m, 2H) 3.83 (s,3H) 3.20 (m, 2H) 2.95 (m, 2H). Mass spectrum: M+H=195.

Step 3. Preparation of 7-methoxy-3-(trifluoroacetyl)thiochroman-4-one.

7-Methoxythiochroman-4-one from Step 2 (1.13 g, 5.8 mmol) and ethyltrifluoroacetate (0.87 g, 6.1 mmol) were dissolved in ether (15 mL),treated with 25% sodium methoxide (2.13 g, 9.9 mmol), stirred at roomtemperature for 23.0 hours, and treated with 3N HCl. The organic layerwas collected, washed with brine, dried over MgSO₄, concentrated invacuo and recrystallized from dichloromethane/isooctane to give thediketone as a yellow solid (0.60 g, 35%): mp 93°-98° C.; ¹ H NMR (CDCl₃)300 MHz 15.92 (s, 1H) 7.96 (d, J=8.9 Hz, 1H) 6.82 (m, 2H) 3.87 (s, 3H)3.82 (s, 2H); ¹⁹ F NMR (CDCl₃) 300 MHz -71.43 (s). Mass spectrum:M+H=291.

Step 4. Preparation of 4- 1,4-dihydro-7-methoxy-3-(trifluoromethyl)-1!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

4-Sulfonamidophenylhydrazine hydrochloride (0.46 g, 2.1 mmol) was addedto a stirred solution of the diketone from Step 3 (0.57 g, 2.0 mmol) inethanol (5 mL). The reaction was heated to reflux and stirred overnight(21.5 hrs). The reaction mixture was filtered while hot to give thepyrazole as a yellow solid (0.63 g, 72%): mp 201°-206° C.; ¹ H NMR(acetone-d₆) 300 MHz 8.08 (d, J=8.7 Hz, 2H) 7.73 (d, J=8.7 Hz, 2H) 7.09(d, J=2.6 Hz, 1H) 6.84 (d, J=8.7 Hz, 1H) 6.80 (br s, 1H) 6.66 (dd, J=2.6Hz J=8.9 Hz , 1H) 4.07 (s, 2H) 3.83 (s, 3H); ¹⁹ F NMR (acetone-d₆) 300MHz -62.24 (s). High resolution mass spectrum Calc'd. for C₁₈ H₁₄ F₃ N₃O₃ S₂ : 441.0429. Found: 441.0457.

EXAMPLE 14 ##STR351## Step 1. Preparation of3-(3-methylphenylthio)propanoic acid.

3-Thiocresol (9.71 g, 78 mmol) was placed in a flask with acrylic acid(5.65 g, 78 mmol) and stirred at room temperature for 62.9 hours. Thereaction mixture solidified and was dissolved in ether and extractedwith 10% Na₂ CO₃. The aqueous layer was acidified with concentratedhydrochloric acid, extracted with ether, washed with brine, dried overMgSO₄ and concentrated in vacuo to give the3-(3-dimethylphenylthio)propanoic acid (10.13 g , 66%) contaminated withsome acrylic acid as a white solid, which was used without furtherpurification in the next step.

Step 2. Preparation of 7-methylthiochroman-4-one.

3-(3-Methylphenylthio)propanoic acid from Step 1 (10.12 g, 52 mmol) wasdissolved in trifluoroacetic acid (20 mL), treated with trifluoroaceticanhydride (10 mL) and stirred at room temperature for 1.9 hours. Thereaction was poured into 10% Na₂ CO₃ (100 mL), extracted with ether,washed with brine, dried over MgSO₄, and concentrated in vacuo to givean orange oil which was passed through a column of silica gel elutingwith 8% ether/hexane to give 7-methylthiochroman-4-one (2.97 g, 32%) asa yellow oil: ¹ H NMR (CDCl₃) 300 MHz 7.97 (d, J=8.1 Hz, 1H) 7.06 (s,1H) 6.97 (d, J=7.7 Hz, 1H) 3.17 (m, 2H) 2.95 (m, 2H) 2.31 (s, 3H). Massspectrum: M+H=179.

Step 3. Preparation of 7-methyl-3-(trifluoroacetyl)thiochroman-4-one.

7-Methylthiochroman-4-one from Step 2 (2.92 g, 16 mmol) and ethyltrifluoroacetate (2.45 g, 17 mmol) were dissolved in ether (20 mL),treated with 25% sodium methoxide (4.60 g, 21 mmol), stirred at roomtemperature for 15.0 hours and treated with 3N hydrochloric acid (15mL). The organic layer was collected, washed with brine, dried overMgSO₄, concentrated in vacuo, and recrystallized fromdichloromethane/isooctane to give the diketone as a yellow solid (3.05g,68%): mp 68°-72° C.; ¹ H NMR (CDCl₃) 300 MHz 15.73 (s, 1H) 7.89 (d,J=8.1 Hz, 1H) 7.17 (s, 1H) 7.09 (d, J=8.1 Hz, 1H) 3.80 (s, 2H) 2.37 (s,3H); ¹⁹ F NMR (CDCl₃) 300 MHz -71.75 (s). Mass spectrum: M+H=275.

Step 4. Preparation of 4- 1,4-dihydro-7-methyl-3-(trifluoromethyl)-1!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

4-Sulfonamidophenylhydrazine hydrochloride (1.21 g, 5.4 mmol) was addedto a stirred solution of the diketone from Step 3 (1.41 g, 5.1 mmol) inethanol (20 mL). The reaction was heated to reflux and stirred overnight(15.8 hours). The reaction mixture was filtered and the filtrateconcentrated in vacuo, dissolved in ethyl acetate, washed with water andbrine, dried over MgSO₄, reconcentrated in vacuo, and recrystallizedfrom ethyl acetate/isooctane to give the pyrazole as a yellow solid(1.14 g, 52%): mp 251°-252° C.; ¹ H NMR (acetone-d₆) 300 MHz 8.08 (d,J=8.7 Hz, 2H) 7.73 (d, J=8.7 Hz, 2H) 7.36 (s, 1H) 6.79 (m, 4H) 4.06 (s,2H) 2.29 (s, 3H); ¹⁹ F NMR (acetone-d₆) 300 MHz -62.22(s). Highresolution mass spectrum Calc'd. for C₁₈ H₁₄ F₃ N₃ O₂ S₂ : 425.0480.Found: 425.0470.

EXAMPLE 15 ##STR352## Step 1. Preparation of3-(3-chlorophenylthio)propanoic acid.

Acrylic acid (2.66 g, 37 mmol) and 3-chlorothiophenol (4.85 g, 34 mmol)were dissolved in ether (15 mL) and stirred at room temperature for 88.0hours. The reaction mixture solidified, was dissolved in ether andextracted with 5% NaOH. The aqueous layer was acidified withconcentrated hydrochloric acid, extracted with ether, washed with brine,dried over MgSO₄, and concentrated in vacuo to give the3-(3-chlorophenylthio)propanoic acid (2.20 g, 34%): ¹ H NMR (acetone-d₆)300 MHz 7.33-7.40 (m, 3H) 7.24 (m, 1H) 3.25 (t, J=7.1 Hz, 2H) 2.67 (t,J=7.1 Hz, 2H). Mass spectrum: M+H=217.

Step 2. Preparation of 7-chlorothiochroman-4-one.

3-(3-Chlorophenylthio)propanoic acid from Step 1 (2.18 g, 10 mmol) wasdissolved in trifluoroacetic acid (10 mL), treated with trifluoroaceticanhydride (6 mL) and stirred at room temperature for 67.8 hours. Thereaction was concentrated in vacuo and the residue dissolved indichloromethane, extracted with 5% NaOH, dried over MgSO₄, andreconcentrated in vacuo to give a brown oil. The crude oil was passedthrough a column of silica gel with 10% ether/hexane to give a mixtureof 7-chlorothiochroman-4-one and 5-chlorothiochroman-4-one as a yellowoil (1.30 g) which was carried on to the next step without furtherpurification.

Step 3. Preparation of 7-chloro-3-(trifluoroacetyl)thiochroman-4-one.

Ethyl trifluoroacetate (1.02 g, 7.2 mmol) was placed in a round bottomflask and dissolved in ether (10 mL). To the stirred solution was added25% sodium methoxide (1.80 g, 8.3 mmol) followed by7-chlorothiochroman-4-one from Step 2 (1.30 g, 6.5 mmol). The reactionwas stirred at room temperature overnight (17.3 hrs) and treated with 3Nhydrochloric acid (5 mL). The organic layer was collected, washed withbrine, dried over MgSO₄, concentrated in vacuo, and recrystallized fromether/hexane to give the diketone (0.61 g, 32%) as a yellow solid: mp64°-71° C.; ¹ H NMR (CDCl₃) 300 MHz 15.53 (s, 1H) 7.92 (d, J=8.5 Hz, 1H)7.36 (s, 1H) 7.25 (d, J=8.7 Hz, 1H) 3.82 (s, 2H); ¹⁹ F NMR (CDCl₃) 300MHz -71.97 (s). Mass spectrum: M+=294.

Step 4. Preparation of 4- 7-chloro-1,4-dihydro-3-(trifluoromethyl)-1!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

4-Sulfonamidophenylhydrazine hydrochloride (0.43 g, 1.9 mmol) was addedto a stirred solution of the diketone from Step 3 (0.55 g, 1.9 mmol) inethanol (6 mL). The reaction was heated to reflux and stirred for 18.9hours. The reaction mixture was cooled and filtered to give the pyrazoleas a yellow solid (0.15 5 g, 18%): mp 237°-238° C.; ¹ H NMR (acetone-d₆)300 MHz 8.09 (d, J=8.7 Hz, 2H) 7.77 (d, J=8.7 Hz, 2H) 7.59 (d, J=2.0 Hz,1H) 7.10 (dd, J=8.5 Hz J=2.0Hz, 1H) 6.96 (d, J=8.5 Hz , 1H) 6.81 (br s,2H) 4.14 (s, 2H); ¹⁹ F NMR (acetone-d₆) 300 MHz -62.25(s). Highresolution mass spectrum Calc'd. for C₁₇ H₁₁ ClF₃ N₃ O₂ S₂ : 444.9933.Found: 444.9874.

EXAMPLE 16 ##STR353## Step 1. Preparation of3-(trifluoroacetyl)isothiochroman-4-one.

Ethyl trifluoroacetate (3.67 g, 25.8 mmol) was dissolved intetrahydrofuran (15 mL) and treated with 25% sodium methoxide (6.46 g,29.9 mmol) followed by a solution of isothiochroman-4-one (4.15 g, 25.3mmol) in tetrahydrofuran (15 mL). The reaction was stirred at roomtemperature for 70.8 hours and treated with 3N hydrochloric acid (10mL). The organic layer was collected, washed with brine, dried overMgSO₄, concentrated in vacuo, and passed through a column of silica geleluting with 40% ethyl acetate/hexane to give a brown solid (5.40 g,82%): ¹ H NMR (CDCl₃) 300 MHz 15.30 (s, 1H) 7.99 (d, J=7.9 Hz, 1H) 7.54(m, 1H) 7.43 (m, 1H) 7.23 (m, 1H) 3.81 (s, 3H).

Step 2. Preparation of 4- 1,5-dihydro-3-(trifluoromethyl)-2!benzothiopyrano 4 3-c!pyrazol-1-yl!benzenesulfonamide.

4-Sulfonamidophenylhydrazine hydrochloride (0.81 g, 3.6 mmol) was addedto a stirred solution of the diketone from Step 1 (0.83 g, 3.2 mmol) inethanol (10 mL). The reaction was heated to reflux and stirred 2.1hours. The reaction mixture was filtered and the filtrate concentratedin vacuo. The residue was dissolved in ethyl acetate, washed with waterand with brine, dried over MgSO₄, reconcentrated in vacuo, and passedthrough a column of silica gel with 40% ethyl acetate to give thepyrazole (0.15 g, 11%): mp 230°-232° C.; ¹ H NMR (acetone-d₆) 300 MHz8.09 (d, J=8.7 Hz, 2H) 7.85 (d, J=8.9 Hz, 2H) 7.53 (d, J=7.7Hz, 1H) 7.40(t, J=7.5 Hz, 1H) 7.21 (t, J=7.7 Hz, 1H) 6.93 (d, J=7.9 Hz, 1H) 6.79 (brs, 2H) 4.16 (s, 2H); ¹⁹ F NMR (acetone-d₆)) 300 MHz -62.94(s). Highresolution mass spectrum Calc'd. for C₁₇ H₁₂ F₃ N₃ O₂ S₂ : 411.0323.Found: 411.0324.

EXAMPLE 17 ##STR354## Step 1. Preraration ofS-(3-methylbenzyl)-isothiouronium chloride.

Thiourea (26.19 g, 344 mmol) was added to a solution ofα-chloro-m-xylene (48.21 g, 343 mmol) in methanol (50 mL). The reactionwas heated to reflux and additional methanol (10 mL) was added todissolve all of the thiourea. After 64.3 hours, the reaction wasfiltered and dried under vacuum to give a white solid (68.15 g, 92%): mp182°-186° C.; ¹ H NMR (DMSO-d₆) 300 MHz 9.34 (br s, 4H) 7.22 (m, 3H)7.12 (m, 1H) 4.48 (s, 2H) 2.27 (s, 3H).

Step 2. Preparation of 3-(3-methylphenylthio)propanoic acid.

A 250 mL flask was charged with the thiouronium salt from Step 1 (10.99g, 51 mmol), sodium chloroacetate (8.86 g, 76 mmol), ethanol (95 mL) andwater (10 mL). After heating to reflux, a solution of NaOH (9.05 g, 226mmol) in water (50 mL) was added to the reaction dropwise over sevenminutes. After stirring for 3.6 hours. the reaction was acidified withconcentrated hydrochloric acid, extracted with ether, washed with brine,dried over MgSO₄ and concentrated in vacuo to give a white solid (9.95g, 100%): mp 73°-75.50° C.; ¹ H NMR (CDCl₃) 300 MHz 7.16 (m, 4H) 3.83(s, 2H) 3.12 (s, 2H) 2.35 (s, 3H). Mass spectrum: M+=196.

Step 3. Preparation of 7-methylisothiochroman-4-one.

The acid from Step 2 (6.06 g, 31 mmol) was dissolved in trifluoroaceticacid (11 mL), treated with trifluoroacetic anhydride (5 mL) and stirredat room temperature for 0.33 hours. The reaction was poured into 10% Na₂CO₃ (100 mL), extracted with ether, washed with brine, dried over MgSO₄,concentrated in vacuo, and recrystallized from ether/hexane to give7-chloroisothiochroman-4-one (2.25 g, 41%) as a white solid: mp79.5°-82° C.; ¹ H NMR (CDCl₃) 300 MHz 7.97 (d, J=8.1 Hz, 1H) 7.17 (d,J=8.1 Hz, 1H) 7.00 (s, 1H) 3.87 (s, 2H) 3.52 (s, 2H) 2.37 (s, 3H). Massspectrum: M+H=179.

Step 4. Preparation of 7-methyl-3-(trifluoroacetyl)isothiochroman-4-one.

Ethyl trifluoroacetate (1.80 g, 12.7 mmol) was placed in a round bottomflask and dissolved in ether (10 mL). To the stirred solution was added25% sodium methoxide (3.90 g, 18.0 mmol) followed by7-chloroisothiochroman-4-one from Step 3 (2.25 g, 12.6 mmol) dissolvedin ether (10 mL) and tetrahydrofuran (10 mL). The reaction was stirredat room temperature for 24.6 hours and treated with 3N hydrochloricacid. The organic layer was collected, washed with brine, dried overMgSO₄, concentrated in vacuo and passed through a column of silica gelwith 20% ether/hexane to give the diketone (1.93 g, 56%) as a brownsolid: ¹ H NMR (CDCl₃) 300 MHz 15.45 (s, 1H) 7.88 (d, J=8.1 Hz, 1H) 7.25(d, J=8.1 Hz, 1H) 7.06 (s, 1H) 3.77 (s, 2H) 2.43 (s, 2H); ¹⁹ F NMR(CDCl₃) 300 MHz: -72.76 (s). Mass spectrum: M+H=275.

Step 5. Preparation of 4- 1,5-dihydro-7-methyl-3-(trifluoromethyl)-2!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

4-Sulfonamidophenylhydrazine hydrochloride (1.68 g, 7.5 mmol) was addedto a stirred solution of the diketone from Step 4 (1.93 g, 7.0 mmol) inethanol (15 mL). The reaction was heated to reflux and stirred for 15.2hours. The reaction mixture was concentrated in vacuo and the residuedissolved in ethyl acetate, washed with water and with brine, dried overMgSO₄, reconcentrated in vacuo and recrystallized from ethylacetate/isooctane to give the pyrazole as a brown solid (1.48 g, 49%):mp 253°-255° C.; ¹ H NMR (acetone-d₆) 300 MHz 8.08 (d, J=8.7 Hz, 2H)7.83 (d, J=8.7 Hz, 2H) 7.35 (s, 1H) 7.02 (d, J=8.1 Hz, 1H) 6.78 (m, 3H)4.11 (s, 2H) 2.34 (s, 3H); ¹⁹ F NMR (acetone-d₆) 300 MHz -62.94(s). Highresolution mass spectrum Calc'd. for C₁₈ H₁₄ F₃ N₃ O₂ S₂ : 426.0558.Found: 426.05554.

EXAMPLE 18 ##STR355## Step 1. Preparation of 1-4-methylsulfonylphenyl!-7-methyl-3-(trifluoromethyl)-1,5-dihydro-2!benzothiopyrano 4,3-c!pyrazole.

4-(Methylsulfonyl)phenylhydrazine (1.23 g, 6.6 mmol) was converted tothe hydrochloride salt by stirring with a 4N solution of hydrochloricacid in dioxane (10 mL) for 25 minutes. The dioxane was removed invacuo, and the 4-(methylsulfonyl)phenylhydrazine hydrochloride wascombined with the diketone (Example 17, Step 4) (1.12 g, 2.9 mmol) andethanol (20 mL), heated to reflux and stirred for 15.5 hours. Thereaction mixture was filtered while hot and the filtrate wasconcentrated in vacuo. The residue was dissolved in ethyl acetate,washed with water and with brine, dried over MgSO₄, reconcentrated invacuo, and passed through a column of silica gel eluting with 12% ethylacetate/hexane to give the pyrazole (0.31 g, 18%) as a yellow solid: mp207°-209° C.; ¹ H NMR (acetone-d₆) 300 MHz 8.14 (d, J=8.7 Hz, 2H) 7.92(d, J=8.9 Hz, 2H) 7.35 (s, 1H) 7.35 (d, J=8.1 Hz, 1H) 6.83 (d, J=7.9 Hz,1H) 4.11 (s, 2H) 3.23 (s, 3H) 2.34 (s, 3H); ¹⁹ F NMR (acetone-d₆) 300MHz -62.97 (s). High resolution mass spectrum Calc'd. for C₁₉ H₁₅ F₃ N₂O₂ S₂ : 424.0527. Found: 424.0524.

EXAMPLE 19 ##STR356## Step 1. Preparation ofS-(3-chlorobenzyl)-isothiouronium chloride.

3-Chlorobenzyl chloride (24.2 g, 0.15 mol) and thiourea (11.4 g, 0.15mol) were dissolved in methanol (70 mL) and heated to reflux for 16hours. The reaction was cooled to room temperature and a precipitateformed. Ether (150 mL) was added to complete the precipitation ofcompound. The crystals were isolated by filtration and washed with ether(100 mL). After drying in vacuo, 31.9 g (90%) of pureS-(3-chlorobenzyl)-isothiouronium chloride was obtained: ¹ H NMR (CD₃OD) δ=4.43p (s, 2H), 7.36p (s, 3H), 7.47p (s, 1H).

Step 2. Preparation of 3-chlorobenzylmercaptoacetic acid.

S-(3-Chlorobenzyl)-isothiouronium chloride from Step 1 (11.86 g, 50mmol) and chloroacetic acid (7.1 g, 75 mmol) were dissolved in ethanol(100 ml) and heated to 80° C. in a 4-neck flask equipped with nitrogeninlet, condenser and addition funnel. A solution of NaOH (10 g) in H₂ O(100 mL) and ethanol (50 mL) was added dropwise over 1 hour to this hotsolution. The reaction was heated to 100° C. for 4 hours. The reactionwas cooled to room temperature, acidified with concentrated hydrochloricacid (45 mL) and extracted with ether (500 mL). The organic layer waswashed with brine (300 ml), dried over MgSO₄ and concentrated in vacuoto yield 10.84 g (100%) of 3-chlorobenzylmercaptoacetic acid which wasused without further purification: ¹ H NMR (CDCl₃) δ=3.08p (s, 2H),3.80p (s, 2H), 7.23p (m, 3H), 7.34p (s, 1H), 9.07p (broad s, 1H).

Step 3. Preparation of 7-chloroisothiochroman-4-one.

3-Chlorobenzylmercaptoacetic acid from Step 2 (3.35 g) was dissolved intrifluoroacetic acid (50 mL). Trifluoroacetic acid anhydride (25 mL) wasadded and the reaction stirred at reflux, under a nitrogen atmospherefor 16 hours. The solution was carefully poured into 10% Na₂ CO₃solution (500 mL) which was stirring vigorously. The organics wereextracted into ether (500 mL) and washed with brine (300 mL), dried overMgSO₄ and concentrated in vacuo. The resulting brown solid was purifiedby silica gel chromatography eluting with a 0-10% gradient of ethylacetate in hexane to yield 7-chloroisothiochroman-4-one (1.57 g, 51%): ¹H NMR (CDCl₃) δ=3.49p (d, 2H, J=0.8 Hz), 3.8p (s, 2H), 7.16p (m, 1H),7.3p (dd, 1H, J=2.0, 8.4 Hz), 7.96p (d, 1H, J=8.5 Hz).

Step 4. Preparation of 7-chloro-3-(trifluoroacetyl)isothiochroman-4-one.

7-Chloroisothiochroman-4-one from Step 3 (0.3 g, 1.5 mmol) was dissolvedin tetrahydrofuran (15 mL) and cooled to -78° C. A solution of sodiumbistrimethylsilyl amide (1.5 mL of a 1.0M tetrahydrofuran solution) wasadded and the reaction stirred for 0.5 hours at -78° C. Trifluoroacetylimidazole (0.21 mL, 1.8 mmol) was added and the reaction was warmed toroom temperature and stirred under a nitrogen atmosphere for 16 hours.1N Hydrochloric acid (100 mL) was added to the reaction followed byextraction with ether (150 mL). The organics were washed with brine (75mL), dried over MgSO₄ and concentrated in vacuo. The resulting yellowoil was used in the next step without further purification.

Step 5. Preparation of 4- 7-chloro-1,5-dihydro-3-(trifluoromethyl)-2!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

A mixture of the diketone from Step 4 (1.51 mmol) and4-sulphonamidophenylhydrazine hydrochloride (0.41 g, 1.8 mmol) wasdissolved in ethanol (50 mL) and heated to reflux for 16 hours. Thereaction was concentrated in vacuo and the resulting solid was dissolvedin ethyl acetate (200 mL). The organics were washed with water (200 mL)and with brine (150 mL), dried over MgSO₄ and concentrated in vacuo. Theresulting oil was chromatographed on silia gel eluting with a gradientof ethyl acetate (from 10-50%) in hexane to yield pure tricyclicpyrazole (0.25 g, 40%): mp 241°-242° C.; ¹ H NMR (acetone-d₆) δ=4.18p(s, 2H), 6.79p (s, 2H), 6.94p (d, 1H, J=8.5 Hz), 7.26p (dd, 1H, J=2.2,8.4 Hz), 7.6p (d, 1H, J=2.2 Hz), 7.83p (dd, 2H, J=2.1, 6.9 Hz), 8.1p(dd, 2H, J=2.1, 6.7 Hz); ¹⁹ F NMR (acetone-d₆) δ 1-62.94p (s, 3F).

EXAMPLE 20 ##STR357## Step 1. Preparation ofS-(3-methoxyphenylmethyl)-isothiouronium chloride.

A solution of 3-methoxybenzyl chloride (15.65 g, 0.1 mol) and thiourea(7.6 g, 0.1 mol) were dissolved in 40 mL of ethanol and heated to refluxfor 16 hours, during this time the isothiouronium salt crystallized. Thethiouronium chloride was isolated by filtration and recrystallized fromether and ethanol (21.85 g, 94%, mp 172.5°-174.0° C.). This material wasused directly in the next step.

Step 2. Preparation of 3-methoxybenzylmercaptoacetic acid.

The thiouronium chloride from Step 1 (20.00 g, 86 mmol) and chloroaceticacid (11.07 g, 95 mmol) were dissolved in ethanol (100 mL) and heated to80° C. in a 4-neck flask equipped with nitrogen inlet, condenser andaddition funnel. A solution of NaOH (10 g) in water (100 mL) and ethanol(50 mL) was added dropwise over 1 hour to the hot solution. The reactionwas heated to 100° C. for 4 hours. The reaction was cooled to roomtemperature, acidified with concentrated hydrochloric acid (45 mL), andextracted with ether (500 mL). The organic layer was washed with brine(300 mL), dried over MgSO₄ and concentrated in vacuo to yield an oilthat was vacuum distilled to provide 16.41 g (90%) of pure acid: bp160°-170° C. at 0.2 mm; ¹ H NMR (CDCl₃ /300 MHz) 3.1p (s, 2H), 3.8p (s,3H), 3.82p (s, 2H), 6.8p (m, 1H), 6.91p (s, 1H), 6.96p (m, 1H), 7.23p(t, 1H, J=7.7 Hz), 8.33p (broad s, 1H), 11.1(brs, 1H).

Step 3. Preparation of 7-methoxyisothiochroman-4-one.

3-methoxybenzylmercaptoacetic acid from Step 2 (10.82 g) was dissolvedin trifluoroacetic acid (50 mL). Trifluoroacetic acid anhydride (25 mL)was added and the reaction stirred under a nitrogen atmosphere for 0.25hours. At this time, TLC showed no starting material. The solution wascarefully poured into 10% Na₂ CO₃ solution (500 mL) which was stirringvigorously. The organics were extracted into ether (500 mL) and washedwith brine (300 mL), dried over MgSO₄ and concentrated in vacuo. Theresulting brown solid was purified by silica gel chromatography elutingwith 20% ethyl acetate in hexane to yield 7-methoxyisothiochroman-4-one(4.84 g, 49%): ¹ H NMR (CDCl₃) δ=3.48p (t, 2H, J=0.8 Hz), 3.83p (s, 3H),3.84p (s, 2H), 6.6p (d, 1H, J=2.4 Hz), 6.83p (dd, 1H, J=2.4, 8.9 Hz),8.0p (d, 1H, J=8.9 Hz).

Step 4. Preparation of7-methoxy-3-(trifluoroacetyl)-isothiochroman-4-one.

7-Methoxyisothiochroman-4-one from Step 3 (0.58 g, 3.0 mmol) wasdissolved in tetrahydrofuran (30 mL) and cooled to -78° C. A solution ofsodium bistrimethylsilylamide (3.0 mL of a 1.0M tetrahydrofuransolution) was added and the reaction stirred for 0.5 hours at -78° C.Trifluoroacetyl imidazole (0.41 mL, 3.6 mmol) was added and the reactionwas warmed to room temperature and stirred under a nitrogen atmospherefor 16 hours. At this time, 1N hydrochloric acid (200 mL) was added tothe reaction followed by extraction with ether (250 mL). The organicswere washed with brine (150 mL), dried over MgSO₄ and concentrated invacuo. The resulting yellow oil (0.42 g, 48%) was used without furtherpurification.

Step 5. Preparation of 4- 1,5-dihydro-7-methoxy-3-(trifluoromethyl)-2!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

A solution of the dione from Step 4 (0.42 g, 1.4 mmol) and4-sulphonamidophenylhydrazine hydrochloride (0.42 g, 1.8 mmol) weredissolved in ethanol (50 mL) and heated to reflux for 16 hours. Thereaction was concentrated in vacuo and the resulting solid was dissolvedin ethyl acetate (200 mL). The organics were washed with H₂ O (200 mL)followed by brine (150 ml), dried over MgSO₄ and concentrated in vacuo.The resulting oil was chromatographed on silica gel eluting with agradient of ethyl acetate (from 20-50%) in hexane to yield puretricyclic pyrazole (0.25 g, 41%): mp 268°-270° C.; ¹ H NMR (acetone-d₆)δ=3.84p (s, 3H), 4.12p (s, 2H), 6.8p (m, 3H), 7.1p (d, 1H, J=2.4 Hz),7.81p (d, 2H, J=6.6 Hz), 7.82p (s, 2H), 8.08p (dd, 2H, J=1.9, 6.6 Hz);¹⁹ F NMR (acetone-d₆) δ=-62.9p (s, 3F).

EXAMPLE 21 ##STR358## Step 1. Preparation ofS-(5-chloro-2-thienylmethyl)-isothiouronium chloride.

2-Chloro-5-(chloromethyl)thiophene (14.5 g, 87 mmol) and thiourea (6.6g, 87 mol) were dissolved in methanol (30 mL) and heated to reflux for16 hours. The reaction was cooled to room temperature and a precipitateformed. Ether (150 mL) was added to complete the precipitation ofcompound. The crystals were isolated by filtration and washed with ether(100 mL). After drying in vacuo, 19.0 g (90%) of pureS-(5-chloro-2-thienylmethyl)-isothiouronium chloride were obtained: ¹ HNMR (CD₃ OD) δ=4.83p (s, 2H), 6.87p (d, 1H, J=3.8 Hz), 6.96p (d, 1H,J=3.2 Hz).

Step 2. Preparation of 5-chloro-2-thienylmethylmercaptoacetic acid.

The compound from Step 1 (12.16 g, 50 mmol) and chloroacetic acid (7.1g, 75 mmol) were dissolved in ethanol (100 mL) and heated to 80° C. in a4-neck flask equipped with nitrogen inlet, condenser and additionfunnel. A solution of NaOH (10 g) in water (100 mL) and ethanol (50 mL)was added dropwise over 1 hour to the hot solution. The reaction washeated to 100° C. for 4 hours. The reaction was cooled to roomtemperature, acidified with concentrated hydrochloric acid (45 mL) andextracted with ether (500 mL). The organic layer was washed with brine(300 mL), dried over MgSO₄ and concentrated in vacuo to yield 11.14 g(100%) of pure acid which was used without further purification: ¹ H NMR(CDCl₃) δ=3.2p (s, 2H), 3.98p (s, 2H), 6.73p (d, 1H, J=3.6 Hz), 6.77p(d, 1H, J=3.8 Hz).

Step 3 Preparation of 6-chloro-5,6-dihydro-4H-thieno2,3-b!thiopyran-4-one.

The acid from Step 2 (4.45 g) was dissolved in trifluoroacetic acid (45mL). Trifluoroacetic acid anhydride (20 mL) was added and the reactionwas stirred under a nitrogen atmosphere for 0.25 hours. At this time,TLC showed no starting material. The solution was carefully poured into10% Na₂ CO₃ solution (600 mL) which was stirring vigorously. Theorganics were extracted into ethyl acetate (500 mL), washed with brine(300 mL), dried over MgSO₄ and concentrated in vacuo. The resultingbrown solid was purified by SiO₂ chromatography eluting with 10% ethylacetate in hexane to yield of pure intermediate (2.5 g, 61%): ¹ H NMR(CDCl₃) δ=3.33p (d, 2H, J=0.6 Hz), 3.78p (s, 2H), 7.1p (s, 1H).

Step 4 Preparation of 6-chloro-5,6-dihydro-3-trifluoroacetyl-4H-thieno2,3-b!thiopyran-4-one.

The compound from Step 3 (1.03 g, 5.0 mmol) was dissolved intetrahydrofuran (50 mL) and cooled to -78° C. A solution of sodiumbistrimethylsilylamide (5.0 mL of a 1.0M tetrahydrofuran solution) wasadded and the reaction stirred for 0.75 hours at -78° C. Trifluoroacetylimidazole (0.68 mL, 6.0 mmol) was added and the reaction was warmed toroom temperature and stirred under a nitrogen atmosphere for 16 hours.At this time, 1N hydrochloric acid (300 mL) was added to the reactionfollowed by extraction with ether (350 mL). The organics were washedwith brine (200 mL), dried over MgSO₄ and concentrated in vacua. Theresulting yellow oil was used without further purification.

Step 5 Preparation of 4- 7-chloro-1,5-dihydro-3-trifluoromethyl-thieno3',2':4,5!thiopyrano 3,2-c!pyrazol-1-yl!benzenesulfonamide.

The compound from Step 4 (5.5 mmol) and 4-sulphonamidophenylhydrazinehydrochloride (1.47 g, 6.6 mmol) were dissolved in ethanol (100 mL) andheated to reflux for 16 hours. The reaction was concentrated in vacuaand the resulting solid dissolved in ethyl acetate (300 mL). Theorganics were washed with water (300 mL) followed by brine (200 mL) andwere then dried over MgSO₄ and concentrated in vacua. The resulting oilwas chromatographed on silica gel eluting with a gradient of ethylacetate (from 20-40%) in hexane. This product was first crystallizedfrom ethyl acetate and isooctane, then from ethanol and water to yieldpure 4- 7-chloro-1,5-dihydro-3-trifluoromethylthieno3',2':4,5!thiopyrano 3,2-c!pyrazol-1-yl!benzenesulfonamide 0.35 g, 16%from Step 2!: mp 218°-220° C. (dec); ¹ H NMR (CDCl₃) δ=4.0p (s, 2H),6.27p (s, 2H), 7.32p (s, 1H), 7.61(d, 2H, J=7.0 Hz), 8.02p (d, 2H, J=7.0Hz); ¹⁹ F NMR (acetone-d₆) δ=-59.25p (s, 3F).

EXAMPLE 22 ##STR359## Step 1. Preparation of 1-4-(aminosulfonyl)phenyl!-1,4-dihydro- 1!benzothiopyrano4,3-c!pyrazol-3-carboxamide.

The compound from Example 8 (11.31 g, 28.3 mmol) was placed in a 500 mLflask with methanol (200 mL), anhydrous ammonia was bubbled through thesolution, the flask was capped and allowed to stand. After 14 days thereaction was concentrated in vacuo and recrystallized from ethyl acetateto give the carboxamide as yellow solid (10.14 g, 93%): mp 238°-242° C.;¹ H NMR (acetone-d₆) 300 MHz 8.07 (d, J=8.7 Hz, 2H) 7.72 (d, J=8.7 Hz,2H) 7.49 (d, J=7.9 Hz, 1H) 7.30 (br s, 1H) 7.23 (dd, 1H) 7.02 (dd, 1H)6.91 (d, J=7.9 Hz, 1H) 6.80 (br s, 2H) 6.75 (br s, 1H) 4.28 (s, 2H).Mass spectrum: M+H=387.

Step 2. Preparation of 1- 4-(aminosulfonyl)phenyl!-1,4-dihydro-1!benzothiopyrano 4,3-c!pyrazol-3-carbonitrile.

Dimethylformamide (10 mL) (DMF) was placed in a 250 mL flask and cooledto 0° C. Oxalyl chloride (2 mL, 23 mmol) was added and stirred for 15minutes. A solution of the product from Step 1 (3.34 g, 9 mmol) in DMF(13 mL) was added and the reaction was stirred for 0.8 hours, treatedwith pyridine (3.8 mL, 47 mmol), poured into 3N hydrochloric acid (30mL) and filtered to give a solid (2.86 g). The filtrate was extractedwith dichloromethane, washed with 3N hydrochloric acid and withsaturated NaHCO₃, dried over MgSO₄, concentrated in vacuo, combined withthe previously collected solid, purified by flash chromatography onsilica gel eluting with 1% methanol/dichloromethane, and recrystallizedfrom dichloromethane/isooctane to give a solid (2.44 g, mp 220°-222° C.)which was the DMF adduct of the desired product. The DMF adduct (2.44 g)was dissolved in dioxane (18 mL) and treated with a 4N solution ofhydrochloric acid in dioxane (10 mL). The solution was stirred at roomtemperature for 7.25 hours, heated to reflux for 42 hours, filtered, andconcentrated in vacuo. The residue was dissolved in methylene chloride,washed with water, dried over MgSO₄, and reconcentrated in vacuo to givea brown foam (2.43 g) which was a mixture of the desired product and itsadduct with DMF. The mixture was purified by flash chromatography onsilica gel eluting with 40% ethyl acetate/hexane to give the desiredproduct as a white solid (0.62 g, 19%): mp 211°-213° C.; ¹ H NMR(acetone-d₆) 300 MHz 8.10 (d, J=8.5 Hz, 2H) 7.76 (d, J=8.5 Hz, 2H) 7.54(d, J=7.7 Hz, 1H) 7.30 (dd, 1H) 7.07 (dd, 1H) 6.94 (d, J=8.1 Hz, 1H)6.82 (br s, 2H) 4.12 (s, 2H). High resolution mass Calc'd. for C₁₇ H₁₂N₄ O₂ S₂ : 368.0402. Found: 368.0368.

EXAMPLE 23 ##STR360## Step 1. Preparation of2-fluoro-3-methoxyphenyl)-3-oxo-propanoic acid.

A solution of 2-fluoro-3-methoxybenzyl alcohol (1.57 g, 9.22 mmol),chloroacetic acid (1.72 g, 18.2 mmol), and ethanol (0.04 mL) in 20 mL ofanhydrous tetrahydrofuran was added to a mixture of sodium hydride (2.29g, 95.2 mmol) in 10 mL of anhydrous tetrahydrofuran dropwise over 10minutes at 0° C. The cooling bath was removed and the solution warmed toroom temperature and then was heated to reflux for 14 hours. Thesolution was cooled to room temperature, acidified with 3N hydrochloricacid, and extracted with ether. The ethereal phase was washed withbrine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuoto provide a yellow solid (2.04 g, 100%) that was used directly in thenext step: ¹ H NMR (CDCl₃ /300 MHz) 8.60 (brs, 1H), 7.08-6.93 (m, 3H),4.72 (d, J=1.4 Hz, 2H), 4.17 (s, 2H), 3.88 (s, 3H); ¹⁹ F NMR (CDCl₃ /282MHz) -141.50 (t). Mass spectrum M+Li=221.

Step 2. Preparation of 7-methoxy-8-fluoro-isochroman-4-one.

A solution of 2-fluoro-3-methoxyphenyl)-3-oxo-propanoic acid from Step 1(1.96 g, 8.6 mmol) in 4 mL of trifluoroacetic acid and 2 mL oftrifluoroacetic anhydride was stirred at room temperature for 1 hour.The solution was concentrated in vacuo, the residue dissolved in ether,and the ethereal solution was washed with saturated aqueous NaHCO₃,brine, dried over anhydrous MgSO₄, filtered and concentrated in vacuo togive a solid that was purified by flash chromatography to provide 0.37 g(32%) of the desired ketone. The aqueous phase from the NaHCO₃ wasacidified, extracted with ether, washed with brine, dried over anhydrousMgSO₄, filtered, and concentrated in vacuo to provide 1.13 g, ofrecovered 2-fluoro-3-methoxyphenyl)3-oxo-propanoic acid: mp 112°-118°C.; ¹ H NMR (CDCl₃ /300 MHz) 7.86 (dd, J=8.66, 1.41 Hz, 1H), 7.00(apparent t, J=8.26 Hz, 1H), 4.96 (s, 2H), 4.31 (S, 2H), 3.97 (S, 3H);¹⁹ F NMR (CDCl₃ /282 MHz) -142.2 (d). Mass spectrum M+=196.

Step 3. Preparation of7-methoxy-8-fluoro-3-(trifluoroacetyl)isochroman-4-one.

A solution of 7-methoxy-8-fluoro-isochroman-4-one from Step 2 (370 mg,1.76 mmol) and ethyl trifluoroacetate (290 mg, 2.04 mmol) in 8 mL ofanhydrous tetrahydrofuran was treated with a solution of 25% sodiummethoxide in methanol (570 mg, 2.64 mmol). The solution was stirred atroom temperature for 16 hours, treated with excess 3N hydrochloric acid,and extracted with ether. The ethereal extract was washed with brine,dried over anhydrous MgSO₄, filtered and concentrated in vacuo to afford450 mg (88%) of pure7-methoxy-8-fluoro-3-(trifluoroacetyl)isochroman-4-one which was useddirectly in the next step without further purification.

Step 4. Preparation of 4-6-fluoro-1,4-dihydro-7-methoxy-3-(trifluoromethyl)- 1!benzopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide.

7-Methoxy-8-fluoro-3-(trifluoroacetyl)isochroman-4-one from Step 3 (450mg, 1.47 mmol) and 4-sulfonamidophenylhydrazine hydrochloride (430 mg,1.92 mmol) were dissolved in 5 mL of anhydrous ethanol and heated toreflux for 45 minutes. The solution was concentrated in vacuo and theresidue was dissolved in ethyl acetate. The solution was washed with 3Nhydrochloric acid, brine, dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. The residue was crystallized from a mixture ofisooctane and ethyl acetate to afford 4-1,4-dihydro-6-fluoro-7-methoxy-3-(trifluoromethyl)- 1!benzopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide as a white solid (200 mg, 30%): mp289.5°-291.0° C.; ¹ H NMR (acetone d₆ /300 MHz) 8.12 (d, J=8.4 Hz, 2H),7.90 (d, J=8.5 Hz. 2H), 7.07 (dd, J=8.7, 8.5 Hz, 1H), 6.83 (br s, 2H),6.75 (d, J=8.7 Hz, 1H), 5.45 (s, 2H), 3.90 (s, 3H); ¹⁹ F NMR (acetone d₆/282 MHz) -62.51 (s), -140.97 (d). High resolution mass spectrum Calc'd.for C₁₈ H₁₃ F₄ N₃ O₄ S: 443.0563. Found: 443.0570.

EXAMPLE 24 ##STR361## Step 1. Preparation ofS-(3-methylbenzyl)-isothiouronium chloride.

Thiourea (26.19 g, 344 mmol) was added to a solution ofα-chloro-m-xylene (48.21 g, 343 mmol) in methanol (50 mL). The reactionwas heated to reflux and additional methanol (10 mL) was added todissolve all of the thiourea. After 64.3 hours, the reaction wasfiltered and dried in vacuo to give a white solid (68.15 g, 92%): mp182°-186° C. ¹ H NMR (DMSO-d₆ 300 MHz) 9.34 (br s, 4H) 7.22 (m, 3H) 7.12(m, 1H) 4.48 (s, 2H) 2.27 (s, 3H).

Step 2. Preparation of 3-(3-methylphenylthio)propanoic acid.

The thiouronium salt from Step 1 (10.99 g, 51 mmol) was added to sodiumchloroacetate (8.86 g, 76 mmol), ethanol (95 mL), and water (10 mL).After heating to reflux, a solution of NaOH (9.05 g, 226 mmol) in water(50 mL) was added to the reaction dropwise over seven minutes. Afterstirring for 3.6 hours, the reaction was acidified with concentratedhydrochloric acid, extracted with ether, washed with brine, dried overMgSO₄, and concentrated in vacuo to give a white solid (9.95 g, 100%):mp 73°-75.5° C. ¹ H NMR (CDCl₃ 300 MHz) 7.16 (m, 4H) 3.83 (s, 2H) 3.12(s, 2H) 2.35 (s, 3H). Mass spectrum: M+=196.

Step 3. Preparation of 7-methylisothiochroman-4-one.

The acid from Step 2 (6.06 g, 31 mmol) was dissolved in trifluoroaceticacid (11 mL), treated with trifluoroacetic anhydride (5 mL) and stirredat room temperature for 0.33 hour. The reaction was poured into 10% Na₂CO₃ (100 mL) and extracted with ether, washed with brine, dried overMgSO₄, concentrated in vacuo, and recrystallized from ether/hexane togive 7-chloroisothiochroman-4-one (2.25 g, 41%) as a white solid: mp79.5°-82° C. ¹ H NMR (CDCl₃ 300 MHz) 7.97 (d, J=8.1 Hz, 1H) 7.17 (d,J=8.1 Hz, 1H) 7.00 (s, 1H) 3.87 (s, 2H) 3.52 (s, 2H) 2.37 (s, 3H). Massspectrum: M+H=179.

Step 4. Preparation of 7-methyl-3-(difluoroacetyl)isothiochroman-4-one.

Ethyl difluoroacetate (1.27 g, 10.3 mmol) was dissolved in ether (100mL). To the stirred solution was added 25 weight % sodium methoxide(2.47 ml, 10.8 mmol) followed by 7-methylisothiochroman-4-one from Step3 (1.83 g, 10.27 mmol) dissolved in ether (50 mL). The reaction wasstirred at room temperature for 16 hours and treated with 1Nhydrochloric acid. The organic layer was collected, washed with brine,dried over MgSO₄, concentrated in vacuo. The crude product was usedwithout further purification.

Step 5. Preparation of 4- 3-(difluoromethyl)-1,5-Dihydro-7-methyl-2!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

4-Sulfonamidophenylhydrazine hydrochloride (2.67 g, 11.9 mmol) was addedto a stirred solution of the diketone from Step 4 (2.35 g, 9.17 mmol) inethanol (75 mL). The reaction was heated to reflux and stirred for 16hours. The reaction was concentrated in vacuo and the residue wasdissolved in ethyl acetate, washed with water and brine, dried overMgSO₄, concentrated in vacuo, and crystallized from ethylacetate/isooctane to give the pyrazole as a white solid (1.98 g, 53%): ¹H NMR (acetone-d₆ 300 MHz) 2.34 (s, 3H), 4.06 (s. 2H), 6.8 (m, 3H), 6.96(t, 1H, J=54 Hz), 7.0 (m, 1H), 7.34(s, 1H), 7.78 (d, 2H, J=8.66 Hz),8.06 (d, 2H, J=8.66 Hz). ¹⁹ F NMR (acetone-d₆ 282 MHz) -115.5, d, J=54Hz.

EXAMPLE 25 ##STR362## Step 1. Preparation ofS-(3-chlorobenzyl)-isothiouronium chloride.

3-Chlorobenzyl chloride (24.2 g, 0.15 mol) and thiourea (11.4 g, 0.15mol) were dissolved in methanol (70 mL) and heated to reflux for 16hours. The reaction was cooled to room temperature and a precipitateformed. Ether (150 mL) was added to complete the precipitation ofproduct. The crystals were isolated by filtration and washed with ether(100 mL). After drying in vacuo, 31.9 g (90%) of pureS-(3-chlorobenzyl)-isothiouronium chloride was obtained: ¹ H NMR (CD₃OD) 4.43(s, 2H) 7.36(s, 3H) 7.47(s, 1H).

Step 2. Preparation of 3-chlorobenzylmercaptoacetic acid.

S-(3-Chlorobenzyl)-isothiouronium chloride from Step 1 (11.86 g, 50mmol) and chloroacetic acid (7.1 g, 75 mmol) were dissolved in ethanol(100 ml) and heated to 80° C. in a 4-neck flask equipped with nitrogeninlet, condenser and addition funnel. A solution of NaOH (10 g) in H₂ O(100 mL) and ethanol (50 mL) was added dropwise over 1 hour to this hotsolution. The reaction was then heated to 100° C. for 4 hours. Thereaction was cooled to room temperature, acidified with concentratedhydrochloric acid (45 mL) and extracted with ether (500 mL). The organiclayer was washed with brine (300 ml), dried over MgSO₄ and concentratedin vacuo to yield 10.84 g (100%) of 3-chlorobenzylmercaptoacetic acidwhich was used without further purification: ¹ H NMR (CDCl₃ 300 MHz)3.08 (s, 2H) 3.80 (s, 2H) 7.23 (m, 3H) 7.34 (s, 1H), 9.07 (broad s, 1H).

Step 3. Preparation of 7-chloroisothiochroman-4-one.

3-Chlorobenzylmercaptoacetic acid (Step 2) (3.35 g) was dissolved intrifluoroacetic acid (50 mL). Trifluoroacetic acid anhydride (25 mL) wasadded and the reaction was heated at reflux, under nitrogen, for 16hours. The solution was carefully poured into 10% Na₂ CO₃ solution (500mL) which was stirring vigorously. The organics were extracted intoether (500 mL) and washed with brine (300 mL), dried over MgSO₄ andconcentrated in vacuo. The resulting brown solid was purified by SiO₂chromatography, eluting with a 0-10% gradient of ethyl acetate in hexaneto yield 7-chloroisothiochroman-4-one, (1.57 g, 51%): ¹ H NMR (CDCl₃ 300MHz) 3.49 (d, 2H, J=0.8 Hz), 3.8 (s, 2H), 7.16 (m, 1H), 7.3 (dd, 1H,J=2.0, 8.4 Hz), 7.96 (d, 1H, J=8.5 Hz).

Step 4. Preparation of 7-chloro-3-(difluoroacetyl) isothiochroman-4-one.

Ethyl difluoroacetate (1.37 g, 11.1 mmol) was dissolved in diethyl ether(100 mL). To the stirred solution was added 25 weight % sodium methoxide(2.7 ml, 11.7 mmol), followed by 7-chloroisothiochroman-4-one (Step 3)(2.2 g, 11.1 mmol) dissolved in diethyl ether (50 mL). The reaction wasstirred at room temperature for 16 hours, then treated with 1Nhydrochloric acid. The organic layer was collected, washed with brine,dried over MgSO₄, concentrated in vacuo. The crude product was usedwithout further purification.

Step 5. Preparation of 4- 7-chloro-3-(difluoromethyl)-1,5-dihydro-2!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

A mixture of the product from Step 4 (11.1 mmol) and4-sulphonamidophenylhydrazine hydrochloride (3.2 g, 14.4 mmol) weredissolved in ethanol (100 mL) and heated to reflux for 16 hours. Thereaction was concentrated in vacuo and the resulting solid was dissolvedin ethyl acetate (200 mL). The organics were washed with water (200 mL),brine (150 mL), dried over MgSO₄ and concentrated in vacuo. Theresulting oil was chromatographed on SiO₂ eluting with a gradient ofethyl acetate (from 10-50%) in hexane to yield pure tricyclic pyrazole(1.9 g, 40%): .sup. H NMR (acetone-d₆ 300 MHz) 4.13 (s, 2H), 6.8 (s,2H), 6.9 (m, 1H), 7.0 (t, 1H, J=78 Hz), 7.25 (m, 1H), 7.6 (s, 1H), 7.8(d, 2H, J=8.66 Hz), 8.1 (d, 2H, J=8.66 Hz). ¹⁹ F NMR (acetone-d₆ 282MHz) -115.5 (d, J=78 Hz).

EXAMPLE 26 ##STR363## Step 1. Preparation of3-(3-methoxybenzyloxy)acetic acid.

A suspension of sodium hydride (5.49 g, 0.217 mol) in 80 mL of anhydrousTHF was cooled to 0° C. and treated with a solution of 3-methoxybenzylalcohol (10.0 g, 72.4 mmol) and chloroacetic acid (10.26 g, 0.108 mol)in 80 mL of THF over ca. 0.25 hour. The solution was stirred at 0° C.for 2 hours and then warmed to room temperature for 14 hours. Thesolution was cooled to 0° C., treated with 50 mL of 6N HCl and extractedwith dichloromethane. The dichloromethane solution was washed withbrine, dried over anhydrous MgSO₄, filtered and concentrated in vacuo toafford 13.48 g (95%) of pure 3-(3-methoxybenzyloxy)acetic acid that wasused directly in the next step: ¹ H NMR (CDCl₃ 300 MHz) 7.31-7.26 (m,1H), 6.94-6.85 (m, 3H), 4.63 (s, 2H), 4.15 (s, 2H), 3.82 (s, 3H).

Step 2. Preparation of 7-methoxyisochroman-4-one.

A solution of 3-(3-methoxybenzyloxy)acetic acid (Step 1) (6.50 g, 33.1mmol) in 20 mL of trifluoroacetic acid was treated with trifluoroaceticanhydride (5.15 g, 36.4 mmol) and stirred at room temperature for 0.75hour. The solution was concentrated in vacuo and the residue waspurified by flash chromatography over silica gel eluting with 10% ethylacetate in hexane to afford 3.96 g (67%) of 7-methoxyisochroman-4-one: ¹H NMR (CDCl₃ /300 MHz) 8.01 (d, J=8.66 Hz, 1H), 6.90 (dd, J=8.66, 2.42Hz, 1H), 6.65 (d, J=2.42 Hz, 1H), 4.84 (s, 2H), 4.32 (s, 2H), 3.87 (s,3H).

Step 3. Preparation of 4- 1,5-dihydro-7-methoxy-3-(trifluoromethyl)-2!benzopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

A mixture of 7-methoxyisochroman-4-one (3.96 g, 22.2 mmol) and ethyltrifluoroacetate (2.90 mL, 5.8 mmol) was dissolved in 30 mL of diethylether and treated with a solution of 25% sodium methoxide in methanol(5.8 mL, 26.7 mmol). The solution was stirred at room temperature for 1hour. The solution was diluted with 1N HCl and extracted with ethylacetate, washed with brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to afford a solid. The crude reaction product wasdissolved in 50 mL of ethanol and treated with4-sulfonamidophenylhydrazine hydrochloride (5.47 g, 24.4 mmol). Thissolution was heated to reflux for 3.5 hours, cooled to room temperature,diluted with 100 mL of 1N HCl. After cooling the solution to 0° C. forca. 0.5 hour, crystals of pure 4-1,5-dihydro-7-methoxy-3-(trifluoromethyl)- 2!benzopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide formed that were isolated byfiltration and dried in vacuo to afford 7.56 g (80%): mp 275° C. (dec).¹ H NMR (CDCl₃ 300 MHz) 7.91 (d, J=8.66 Hz, 2H), 7.54 (d, J=8.66 Hz,2H), 6.69-6.54 (m, 5H), 5.07 (s, 2H), 3.63 (s, 3H). ¹⁹ F NMR (CDCl₃ 282MHz) -62.01(s). Anal. calc'd. for C₁₈ H₁₄ F₃ N₃ O₄ S: C, 50.82; H, 3.32;N, 9.88; S, 7.54. Found: C, 50.93; H, 3.38; N, 9.94; S, 7.57.

EXAMPLE 27 ##STR364## Step 1. Preparation of3-(3,4,5-trimethoxybenzyloxy)acetic acid.

A suspension of sodium hydride (10.2 g, 0.403 mol) in 80 mL of anhydrousTHF was cooled to 0° C. and treated with a solution of3,4,5-trimethoxybenzyl alcohol (8.00 g, 40.4 mmol) and chloroacetic acid(7.63 g, 80.7 mmol) in 80 mL of THF over 1 hour. The solution wasstirred at 0° C. for 1 hour and heated to reflux for 14 hours. Thesolution was cooled to 0° C., treated with 30 mL of methanol, 10 mL ofwater, and then the solution was extracted with dichloromethane. Thedichloromethane solution was washed with brine, dried over anhydrousMgSO₄, filtered and concentrated in vacua to afford 10.4 g, 100% of pure3-(3-methoxybenzyloxy)acetic acid that was used directly in the nextstep.

Step 2. Preparation of 6,7,8-trimethoxyisochroman-4-one.

A solution of 3-(3,4,5-trimethoxybenzyloxy)acetic acid (Step 1) (10.0 g,39 mmol) in 30 mL of trifluoroacetic acid was treated withtrifluoroacetic anhydride (15 mL) and stirred at room temperature for 20minutes. The solution was concentrated in vacuo and used directly in thenext step without purification: ¹ H NMR (CDCl₃ 300 MHz) 6.56 (s, 2H),4.58 (s, 2H), 4.16 (s, 2H), 3.86 (s, 6H), 3.83 (s, 3H).

Step 3. Preparation of 4-1,5-dihydro-7.8,9-trimethoxy-3-(trifluoromethyl)- 2!benzopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide.

The crude product from Step 2 was dissolved in 40 mL of diethyl ether,mixed with ethyl trifluoroacetate (3.35 mL, 28.1 mmol), treated with 25%sodium methoxide in methanol (10 mL, 30.7 mmol) and stirred at roomtemperature for 16 hours. The solution was diluted with 30 mL of 1N HCl,extracted with ethyl acetate, washed with brine, dried over anhydrousMgSO₄, filtered and concentrated in vacua to afford 6.3 g of an oil. Theoil was dissolved in ethanol, mixed with 4-sulfonamidophenylhydrazinehydrochloride (6.3 g, 28.2 mmol) and the solution was heated to refluxfor 16 hours. The solution was cooled to room temperature, diluted with30 mL of 1N HCl, extracted with ethyl acetate, washed with brine, driedover anhydrous MgSO₄, filtered and concentrated in vacua to afford asolid that showed two major components by TLC. The material was purifiedby flash chromatography over silica gel, eluting with 20% ethyl acetatein hexane to afford 877 mg of material that was crystallized from hexaneto afford 400 mg (2%) of pure 4-1,5-dihydro-6,7,8-trimethoxy-3-(trifluoromethyl)- 2!benzopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide from3-(3,4,5-trimethoxybenzyloxy)acetic acid: mp 130° C. ¹ H NMR (CDCl₃ 300MHz) 7.99 (d, J=8.66 Hz, 2H), 7.63 (d, J=8.66 Hz, 2H), 6.65 (s, 1H),5.13 (s, 2H), 4.83 (s, 2H), 3.92 (s, 3H), 3.76 (s, 3H), 3.26 (s, 3H). ¹⁹F NMR (CDCl₃ 282 MHz) -62.10(s). High resolution mass spectrum calc'd.For C₂₀ H₁₈ F₃ O₆ S: 485.0885. Found: 485.0779.

EXAMPLE 28 ##STR365## Step 1. Preparation of 3-(3-methylbenzyloxy)aceticacid.

A suspension of sodium hydride (1.96 g, 75.6 mmol) in 80 mL of anhydrousTHF was cooled to 0° C. and treated with a solution of 3-methylbenzylalcohol (3.16 g, 25.9 mmol) and chloroacetic acid (3.67 g, 38.8 mmol) in80 mL of THF over ca. 1 hour. The solution was stirred at 0° C. for 1.5hours and heated to reflux for 16 hours. The solution was cooled to 0°C., treated with 50 mL of 6N HCl and extracted with dichloromethane. Thedichloromethane solution was washed with brine, dried over anhyd. MgSO₄,filtered and concentrated in vacuo to afford 2.67 g (57%) of pure3-(3-methylbenzyloxy)acetic acid that was used directly in the nextstep. ¹ H NMR (CDCl₃ 300 MHz) 7.28-7.12 (m, 4H), 4.62 (s, 2H), 4.14 (s,2H), 2.36 (s, 3H).

Step 2. Preparation of 7-methylisochroman-4-one.

A solution of 3-(3-methylbenzyloxy)acetic acid (Step 1) (2.67 g, 14.8mmol) in 25 mL of trifluoroacetic acid was treated with trifluoroaceticanhydride (2.5 mL, 17.8 mmol) and stirred at room temperature for 16hours. The solution was concentrated in vacuo and the residue wasdissolved in dichloromethane, washed with sat. aq. NaHCO₃, brine, driedover anhyd. MgSO₄, filtered and concentrated in vacuo to afford an oil,1.45 g, 60%. Examination of the NMR spectrum revealed that the productwas a 3:1 mixture of 7-methylisochroman-4-one:5-methylisochroman-4-one.Flash chromatography of the mixture eluting with 10% ethyl acetate inhexane provided the desired isomer 7-methylisochroman-4-one ¹ H NMR(CDCl₃ 300 MHz) 7.94 (d, J=7.86 Hz, 1H), 7.22 (d, J=7.86 Hz, 1H), 7.02(s, 1H), 4.85 (s, 2H), 4.35 (s, 2H), 2.42 (s, 3H)!.

Step 3. Preparation of 4- 1,5-dihydro-7-methyl-3-(trifluoromethyl)-2!benzopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

The product from Step 2 was dissolved in 20 mL of diethyl ether, mixedwith ethyl trifluoroacetate (0.12 mL, 9.5 mmol), treated with 25% sodiummethoxide in methanol (2.2 mL, 10.4 mmol) and stirred at roomtemperature for 16 hours. The solution was diluted with 10 mL of 1N HCl,extracted with ethyl acetate, washed with brine, dried over anhydrousMgSO₄, filtered and concentrated in vacuo to afford an oil. The oil wasdissolved in ethanol, mixed with 4-sulfonamidophenylhydrazinehydrochloride (2.12 g, 9.5 mmol) and the solution was heated to refluxfor 3 hours. The solution was cooled to room temperature and dilutedwith 30 mL of 0.5N HCl. The solution was chilled in an ice bath,whereupon crystals formed that were isolated by filtration and dried invacuo to afford 1.27 g, 36% of pure product: mp 285° C. (dec). ¹ H NMR(CDCl₃ 300 MHz) 8.05 (d, J=8.66 Hz, 2H), 7.70 (d, J=8.66 Hz, 2H), 7.05(s, 1H), 6.97 (d, J=7.96 Hz, 1H), 6.77 (d, J=7.96, 1H), 5.20 (s, 2H),2.31 (s, 3H). ¹⁹ F NMR (CDCl₃ 282 MHz) -62.11(s). High resolution massspectrum calc'd. for C₁₈ H₁₅ F₃ N₃ O₃ S (MH⁺): 410.0786. Found:410.0754.

EXAMPLE 29 ##STR366## Step 1. Preparation of 2,6-difluoroanisole.

A solution of 2,6-difluorophenol (30.00 g, 230 mmol) in 2.5N sodiumhydroxide (95 mL, 238 mmol) was treated with dimethylsulfate (33.32 g,264 mmol) and stirred for 3.3 hours at 50° C. Additional dimethylsulfate(13.33 g, 105 mmol) was added and the reaction was stirred another 0.6hour. The reaction mixture was extracted with ethyl acetate, washed with2.5N sodium hydroxide, brine, dried over MgSO₄, and concentrated invacuo to give a clear oil (25.93 g, 78%): ¹ H NMR (CDCl₃ 300 MHz) 6.87(m, 3H) 3.98 (s, 3H); ¹⁹ F NMR (CDCl₃ 282 MHz) -129.48 (t). Massspectrum: M+=144.

Step 2. Preparation of 2,4-difluoro-3-methoxybenzoic acid.

A solution of potassium tert-butoxide (22.74 g, 203 mmol) in anhydroustetrahydrofuran (235 mL) was cooled to -78° C. and treated with a 1.6Msolution of n-butyllithium (120 mL, 192 mmol) in hexanes. After stirringfor 30 minutes, 2,6-difluoroanisole (Step 1) (25.89 g, 180 mmol) wasadded and the reaction was stirred an additional 7.4 hours. The reactionwas poured into dry ice and warmed to room temperature. Water (250 mL)was added, and after extracting with ether (160 mL), the aqueous layerwas acidified with concentrated HCl, and filtered to give a yellow solid(3.71 g, 11%): mp 176°-182° C. ¹ H NMR (CDCl₃ 300 MHz) 7.70 (m, 1H) 6.98(m, 1H) 4.01 (s, 3H); ¹⁹ F NMR (CDCl₃ 282 MHz) -119.06 (m) -123.33 (m).mass spectrum: M+Li=195.

Step 3. Preparation of 2,4-difluoro-3-methoxybenzyl alcohol.

A solution of 2,4-difluoro-3-methoxybenzoic acid (Step 2) (3.65 g, 19mmol) in anhydrous tetrahydrofuran (24 mL) was cooled in an ice bath,and treated with borane dimethyl sulfide complex (4 mL, 40 mmol). Thereaction was stirred at room temperature for 17 hours, quenched by theslow addition of methanol, and concentrated in vacuo. The residue wasdissolved in ethyl acetate, washed with NaHCO₃, brine, dried over MgSO₄,and concentrated in vacuo to give a brown oil (2.93 g, 87%): ¹ H NMR(CDCl₃ 300 MHz) 7.01 (m, 1H) 6.86 (m, 1H) 4.66 (s, 2H) 3.97 (s, 3H); ¹⁹F NMR (CDCl₃ 282 MHz) -129.67(m) -135.09 (m). Mass spectrum: M+=174.

Step 4. Preparation of 2,4-difluoro-3-methoxybenzyl chloride.

A solution of 2,4-difluoro-3-methoxybenzyl alcohol (Step 3) (2.93 g, 17mmol) in concentrated HCl (15 mL) was treated with HCl gas for 3minutes. The reaction was stirred at room temperature (21 hours). Thereaction mixture was extracted with ether, dried over MgSO₄, andconcentrated in vacuo to give a brown oil (2.30 g, 71%): ¹ H NMR (CDCl₃300 MHz) 7.03 (m, 1H) 6.89 (m, 1H) 4.58 (s, 2H) 4.01 (s, 3H); ¹⁹ F NMR(CDCl₃ 282 MHz) -127.88 (m) -132.78 (m). Mass spectrum: M+=192.

Step 5. Preparation of S-(2,4-difluoro-3-methoxybenzyl)-isothiouroniumchloride.

Thiourea (0.90 g, 12 mmol) was added to a solution of2,4-difluoro-3-methoxybenzyl chloride (Step 4) (2.30 g, 12 mmol) inmethanol (7 mL). The reaction was heated to reflux for 2.9 hours andconcentrated in vacuo to give a white solid (3.18 g, 100%): mp 144°-151°C. ¹ H NMR (DMSO-d₆ 300 MHz) 9.35 (br. d, 3H) 7.26 (m, 1H) 7.15 (m, 1H)4.57 (s, 2H) 3.91 (s, 3H); ¹⁹ F NMR (DMSO-d₆ 282 MHz) -128.73 (m)-131.41 (m).

Step 6. Preparation of 3-(2.4-difluoro-3-methoxyphenylthio)propanoicacid.

A 100 mL flask was charged with the thiouronium salt from Step 5 (3.18g, 12 mmol), sodium chloroacetate (2.36 g, 20 mmol), ethanol (10 mL),and water (10 mL). After heating to reflux, a solution of NaOH (2.51 g,63 mmol) in water (10 mL) was added to the reaction dropwise. Afterstirring for 15.5 hours, the reaction was acidified with concentratedHCl, extracted with ether, washed with brine, dried over MgSO₄,concentrated in vacuo, and recrystallized from ether/hexane to give abrown oil (2.33 g, 70%): ¹ H NMR (CDCl₃ 300 MHz) 8.4 (br. s, 1H) 6.98(m, 1H) 6.85 (m, 1H) 3.99 (s, 3H) 3.85 (s, 2H) 3.17 (s, 2H); ¹⁹ F NMR(CDCl₃ 282 MHz) -129.33 (m) -132.16 (m). Mass spectrum: M+Li=255.

Step 7. Preparation of 6,8-difluoro-7-methoxyisothiochroman-4-one.

The acid from Step 6 (2.30 g, 9.3 mmol) was dissolved in trifluoroaceticacid (10 mL), treated with trifluoroacetic anhydride (5 mL) and stirredat room temperature for 1.3 hours. The reaction was poured into 10% Na₂CO₃ (150 mL) and extracted with ethyl acetate, washed with brine, driedover MgSO₄, and concentrated in vacuo to give a brown solid (0.45 g)which was used in the next step without further purification.

Step 8. Preparation of6,8-difluoro-7-methoxy-3-(trifluoroacetyl)isothiochroman-4-one.

Ethyl trifluoroacetate (0.30 g, 2.1 mmol) was added to a solution of theisothiochromanone from Step 7 (0.45 g, 2.0 mmol) in ether (5 mL). Thereaction was treated with 25 weight % NaOMe (0.52 g, 2.4 mmol) andstirred at room temperature for 6.5 hours, then treated with 3N HCl. Theorganic layer was collected, washed with brine, dried over MgSO₄, andconcentrated in vacuo to give a brown oil (0.43 g) which was used in thenext step without further purification.

Step 9. Preparation of 4-6,8-difluoro-1,5-dihydro-7-methoxy-3-(trifluoromethyl) 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide.

The 4-sulfonamidophenylhydrazine hydrochloride (0.38 g, 1.7 mmol) wasadded to a stirred solution of the diketone (Step 8) (0.43 g, 1.3 mmol)in ethanol (10 mL). The reaction was heated to reflux and stirred for16.6 hours. The reaction mixture was filtered, and the filtrate wasconcentrated in vacuo, dissolved in ethyl acetate, washed with water andbrine, dried over MgSO₄, concentrated in vacuo, and passed through acolumn of silica gel to give the pyrazole as a brown oil (0.23 g, 37%):¹ H NMR (acetone-d₆ 300 MHz) 8.11 (d, J=8.7 Hz, 2H) 7.87 (d, J=8.7 Hz,2H) 6.84 (br s, 2H) 6.57 (d, J=11.9 Hz, 1H) 4.20 (s, 2H) 4.03 (t, J=1.0Hz, 3H); 19F NMR (acetone-d₆ 282 MHz) -63.33 (s) -130.85 (m) -132.61(m). High resolution mass spectrum calc'd. for C₁₈ H₁₂ F₅ N₃ O₃ S₂ :477.0240. Found: 477.0205.

EXAMPLE 30 ##STR367## Step 1. Preparation of(3-methylphenyl)-3-oxo-propanoic acid.

A solution of 3-methylbenzyl alcohol (4.93 g, 40 mmol), chloroaceticacid (7.68 g, 81 mmol), and ethanol (0.04 mL) in 100 mL of anhydroustetrahydrofuran was added to a mixture of sodium hydride (16.12 g, 403mmol) in 50 mL anhydrous tetrahydrofuran dropwise over 55 minutes at 0°C. The cooling bath was removed and the solution was heated to refluxfor 14.25 hours. The solution was cooled to room temperature, quenchedwith water and extracted with ether. The aqueous layer was acidified,extracted with ether, washed with brine, dried over MgSO₄, andconcentrated in vacuo to give (3-methylphenyl)-3-oxo-propanoic acid asan orange oil (6.58 g) which also contained chloroacetic acid. The oilwas used in the next step without purification.

Step 2. Preparation of 7-methylisochroman-4-one.

The acid from Step 1 (6.58 g, 36 mmol) was dissolved in trifluoroaceticacid (20 mL), treated with trifluoroacetic anhydride (11 mL) and stirredat room temperature for 14.75 hours. The reaction was poured into 10%Na₂ CO₃ (150 mL) and extracted with ether, washed with brine, dried overMgSO₄, concentrated in vacuo, and passed through a column of silica gelwith 15% ethyl acetate/hexane to give a yellow solid (1.09 g, 18%): ¹ HNMR (CDCl₃ 300 MHz) 7.95 (d, J=7.9 Hz, 1H) 7.23 (d, J=7.9 Hz, 1H) 7.02(s, 1H) 4.85 (s, 2H) 4.34 (s, 2H) 2.42 (s, 3H).

Step 3. Preparation of 3-(difluoroacetyl)-7-methylisochroman-4-one.

Ethyl difluoroacetate (1.02 g, 8.2 mmol) was added to a solution of theisochromanone from Step 2 (1.07 g, 6.6 mmol) in ether (20 mL). Thereaction was treated with 25 weight % NaOMe (1.89 g, 8.7 mmol) andstirred at room temperature for 3.1 hours. The reaction mixture wasfiltered to give a yellow solid which was dissolved in 3N HCl, extractedwith ether, washed with brine, dried over MgSO₄, and concentrated invacuo to give a yellow solid (0.79 g) which was used in the next stepwithout further purification.

Step 4. Preparation of 4- 3-(difluoromethyl)-1,5-dihydro-7-methyl2!benzopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

4-Sulfonamidophenylhydrazine hydrochloride (0.77 g, 3.4 mmol) was addedto a stirred solution of the diketone from Step 3 (0.75 g, 3.1 mmol) inethanol (10 mL). The reaction was heated to reflux and stirred for 2.25hours. The reaction mixture was filtered while hot and recrystallizedfrom ethyl acetate/hexane to give a yellow solid (0.41 g, 34%): mp178°-179° C. (dec).¹ H NMR (DMSO-d₆ 300 MHz) 8.00 (d, J=8.7 Hz, 2H) 7.84(d, J=8.5 Hz, 2H) 7.56 (br s, 2H) 7.25 (s, 1H) 7.12 (t, J=53.6 Hz, 1H)7.08 (d, J=8.1 Hz, 1H) 6.72 (d, 8.1 Hz) 5.28 (s, 2H) 2.29 (s, 3H); ¹⁹ FNMR (DMSO-d₆ 282 MHz) -114.42 (d). High resolution mass spectrum calc'd.for C₁₈ H₁₅ F₂ N₃ O₃ S: 391.0802. Found: 391.0798.

EXAMPLE 31 ##STR368## Step 1. Preparation ofS-(3-fluorobenzyl)-isothiouronium chloride.

A solution of 3-fluorobenzyl chloride (49.95 g, 0.346 mol) dissolved in60 mL of anhydrous methanol was treated portion wise with thiourea(26.30 g, 0.346 mol) over a period of 0.25 hour at room temperature. Thesolution was warmed to reflux for 0.5 hour, cooled to 5° C. and theproduct was isolated by filtration to afford 59.17 g. Concentration ofthe filtrate and chilling in an ice bath afforded an additional 9.93 gof pure S-(3-fluorobenzyl)isothiouronium chloride (96%): mp 201°-203° C.

Step 2. Preparation of 3-(3-fluorophenylthio)propanoic acid.

S-(3-Fluorobenzyl)-isothiouronium chloride from step 1 (25.0 g, 94 mmol)was added to sodium chloroacetate (16.4 g, 141 mmol), sodium hydroxidepellets (15.0 g, 376 mmol), ethanol (150 mL), and water (100 mL). Thismixture was stirred for 16 hours at room temperature, then concentratedhydrochloric acid was added to pH 1. The solution was extracted withether (2×100 mL), combined and washed with brine, dried over MgSO₄, andconcentrated. A brown solid was recrystallized from ether/hexanes (18.7g, 95%): mp 86°-88° C.

Step 3. Preparation of 7-fluoroisothiochroman-4-one.

3-(3-Fluorophenylthio)propanoic acid from step 2 (18.0 g, 90 mmol) wasdissolved in trifluoroacetic acid (30 mL), treated with trifluoroaceticanhydride (90 mL) and heated to reflux for 16 hours. Ether (200 mL) wasadded, and the mixture was washed with saturated aqueous NaHCO₃ solution(2×150 mL) and water. After drying over MgSO₄, the solution wasconcentrated to a brown solid (13.0 g, 79%). This material was used inthe next step without further purification or characterization.

Step 4. Preparation of 3-difluoroacetyl-7-fluoro-isothiochroman-4-one.

7-Fluoroisothiochroman-4-one from step 3 (2.0 g, 11 mmol) was dissolvedin anhydrous ethyl ether (50 mL). Sodium methoxide 25% in methanol (2.61g, 12 mmol) and ethyl difluoroacetate (1.49 g, 12 mmol) were added.After stirring for 16 hours at room temperature the mixture was washedwith 1N hydrochloric acid, brine, and water, dried over MgSO₄ andconcentrated. This crude material was used in the next step withoutfurther purification or characterization.

Step 5. Preparation of 4- 3-(difluoromethyl)-1,5-dihydro-7-fluoro-2!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

7-Fluoro-3-(difluoroacetyl)isothiochroman-4-one from Step 4 (2.9 g, 11mmol) was dissolved in ethanol (100 mL), and4-sulfonamidophenylhydrazine hydrochloride (2.68 g, 12 mmol) was added.The mixture was heated to reflux for 16 hours. After cooling, water wasadded until crystals appeared. A dark brown solid was collected byfiltration (1.7 g, 37%): mp 260°-262° C. ¹ H NMR (DMSO-d₆ 300 MHz) 7.96(d, J=8.4 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.54 (s, 2H), 7.42 (dd,J=2.7, 9.3 Hz, 1H), 7.17 (t, J=53.7 Hz, 1H), 7.09 (dt, J=2.4, 8.4 Hz,1H), 6.77 (dd, J=5.4, 8.7 Hz, 1H), 4.15 (s, 2H). Anal. calc'd. for C₁₇H₁₂ N₃ S₂ O₂ F₃ : C, 49.63; H, 2.94; N, 10.21. Found: C, 49.55; H, 2.95;N, 10.14.

EXAMPLE 32 ##STR369## Step 1. Preparation of7-fluoro-3-trifluoroacetyl)isothiochroman-4-one.

7-Fluoroisothiochroman-4-one (Example 31, step 3) (1.82 g, 10 mmol) wasdissolved in anhydrous ethyl ether (50 mL). Sodium methoxide 25% inmethanol (2.38 g, 11 mmol) and ethyl trifluoroacetate (1.56 g, 11 mmol)were added. After stirring for 16 hours at room temperature the mixturewas washed with 1N hydrochloric acid, brine, and water, dried over MgSO₄and concentrated. This crude material was used in the next step withoutfurther purification or characterization.

Step 2. Preparation of 1,5-dihydro-7-fluoro-1-(4-methylsulfonyl)phenyl!-3-(trifluoromethyl)- 2!benzothiopyrano4,3,c!pyrazole.

7-Fluoro-3-trifluoroacetyl)isothiochroman-4-one (2.9 g, 11 mmol) fromStep 1 was dissolved in ethanol (100 mL) andp-methanesulfonylphenylhydrazine hydrochloride (2.45 g, 11 mmol) wasadded. The mixture was heated to reflux for 16 hours, and concentrated.The resultant solid was dissolved in ethyl acetate and washed with brineand water, dried over MgSO₄ and concentrated. A dark brown solid wasrecrystallized from ethyl acetate/hexanes (1.4 g, 32%): mp 193°-195° C.¹ H NMR (DMSO-d₆ 300 MHz) 8.10 (d, J=8.7 Hz, 2H), 7.86 (d, J=8.7 Hz,2H), 7.44 (dd, J=2.7, 9.3 Hz, 1H), 7.09 (dt, J=2.7, 8.7 Hz, 1H), 6.79(dd, J=5.7, 8.7 Hz, 1H), 4.2 (s, 2H), 3.27(s, 3H). Anal. calc'd. for C₁₈H₁₂ N₂ S₂ O₂ F₄ : C, 50.46; H, 2.82; N, 6.54. Found: C, 50.54; H, 2.84;N, 6.57.

EXAMPLE 33 ##STR370## Step 1. Preparation of 2,3-methylenedioxybenzoicacid.

1,3-Benzodioxole (12.2 g, 100 mmol) was dissolved in tetrahydrofuran(150 mL). This mixture was cooled to -78° C. under nitrogen withstirring while n-butyllithium 1.6M in hexane (69 mL, 110 mmol) was addeddropwise maintaining the temperature below -50° C. Potassium t-butoxide(12.34 g, 110 mmol) was added and the mixture stirred at -78° C. for0.25 hour when dry solid carbon dioxide was added. The cooling bath wasremoved and the mixture was stirred for an additional hour, when it waspoured into 250 mL of 1N hydrochloric acid. The mixture was extracted(3×100 mL) with ethyl acetate, combined and the organic portions wereextracted into 2.5N sodium hydroxide solution (2×50 mL). The combinedbasic aqueous layers were acidified to pH 3 with 1N hydrochloric acidand extracted with ethyl acetate (3×50 mL). The combined organic layerswere washed with water, dried over MgSO₄ and concentrated. A light brownsolid was recrystallized from ethyl acetate/hexanes (2.9 g, 17%): mp224°-227° C. ¹ H NMR (DMSO-d₆ 300 MHz) 12.9 (bs, 1H), 7.26 (dd, J=1.2,8.1 Hz, 1H), 7.10 (dd, J=0.9, 7.5 Hz, 1H), 6.87 (dd, J=8.1, 7.8 Hz, 1H),6.10 (s, 2H). Anal. calc'd for C₈ H₆ O₄ : C, 57.84; H, 3.64. Found: C,57.70; H, 3.73.

Step 2. Preparation of 2,3-methylenedioxybenzyl alcohol.

2,3-Methylenedioxybenzoic acid from Step 1 (2.8 g, 17 mmol) wasdissolved in tetrahydrofuran (100 mL) and boranedimethyl sulfide complex(10M) was added (5.0 mL, 50 mmol). This mixture was stirred for 16 hourswhen methanol was added dropwise to destroy unreacted borane. Ethylacetate (100 mL) was added and the mixture was washed with saturatedaqueous NaHCO₃ solution and water twice, dried over MgSO₄, andconcentrated to 2.4 g of a light brown solid. This material was used inthe next step without further purification or characterization.

Step 3. Preparation of S-(2,3-methylenedioxybenzyl)-isothiouroniumchloride.

A solution of 2,3-methylenedioxybenzyl alcohol from Step 2 (2.4 g, 16mmol) was dissolved in tetrahydrofuran (25 mL). Triethylamine (2.43 g,24 mmol) was added followed by the dropwise addition of methanesulfonylchloride (2.27 g, 20 mmol). After stirring at room temperature for 4hours, thiourea (1.3 g, 16 mmol) and methanol (50 mL) were added. Themixture was heated to reflux for 16 hours, concentrated and used in thenext step without further purification or characterization.

Step 4. Preparation of 3-(2,3-methylenedioxyphenylthio)propanoic acid.

S-(2,3-Methylenedioxybenzyl)-isothiouronium chloride from Step 3 (3.4 g,16 mmol), sodium chloroacetate (2.8 g, 24 mmol), sodium hydroxidepellets (2.6 g, 64 mmol), ethanol (25 mL), and water (40 mL) werecombined and stirred for 16 hours at room temperature. Concentratedhydrochloric acid was added to pH 1, and the solution was extracted withether (4×50 mL). The combined ethereal layers were washed with 1Nhydrochloric acid, dried over MgSO₄, and concentrated (3.62 g, 95%).This mixture was used in the next step without further purification orcharacterization.

Step 5. Preparation of 6,7-methylenedioxyisothiochroman-4-one.

3-(2,3-Methylenedioxyphenylthio)propanoic acid from Step 4 (3.62 g, 16mmol) was dissolved in trifluoroacetic acid (5 mL), treated withtrifluoroacetic anhydride (15 mL) and stirred at room temperature for 16hours. After neutralizing with saturated aqueous NaHCO₃, the solutionwas extracted with ethyl acetate (3×50 mL). The combined organicextracts were washed with brine and concentrated. Purification wasperformed by flash column chromatography eluting with (4:1)hexanes:ethyl acetate. The appropriate fractions were concentrated andrecrystallized from ethyl acetate/hexanes to yield a brown solid (0.5 g,15%): mp 114°-116° C. ¹ H NMR (DMSO-d₆ 300 MHz) 7.56 (d, J=8.4 Hz, 1H),6.95 (d, J=8.1 Hz, 1H), 6.16 (s, 2H), 3.87(s, 2H), 3.57(s, 2H). Anal.calc'd. for C₁₀ H₈ O₃ S: C, 57.68; H, 3.87. Found: C, 57.59; H, 3.93

Step 6. Preparation of 6,7-methylenedioxy-3-(trifluoroacetyl)isothiochroman-4-one.

6,7-Methylenedioxyisothiochroman-4-one from Step 5 (0.44 g, 2.1 mmol)was dissolved in anhydrous ethyl ether (50 mL). Sodium methoxide 25% inmethanol (0.54 g, 2.5 mmol) and ethyl trifluoroacetate (0.36 g, 2.5mmol) were added. After stirring for 16 hours at room temperature themixture was washed with 1N hydrochloric acid, brine, and water, driedover MgSO₄ and concentrated. This crude material was used in the nextstep without further purification or characterization.

Step 7. Preparation of 4- 1,5-dihydro-7-fluoro-3-(difluoromethyl)-2!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

6,7-Methylenedioxy-3-(trifluoroacetyl)isothiochroman-4-one from Step 6(0.64 g, 2.1 mmol) was dissolved in ethanol (100 mL) and4-sulfonamidophenylhydrazine hydrochloride (0.56 g, 2.5 mmol) was added.The mixture was heated to reflux for 16 hours, and concentrated. Theresultant oily solid was dissolved in ethyl acetate and washed withbrine and water, dried over MgSO₄ and concentrated. Purification wasachieved by flash column chromatography eluting with (1:1) ethylacetate:hexanes. The appropriate fractions were concentrated andrecrystallized from ethyl acetate/hexanes. The product was a light brownsolid (0.2 g, 21%): mp 272°14 274° C. ¹ H NMR (DMSO-d₆ 300 MHz ) 7.98(d, J=8.4 Hz, 2H), 7.78 (d, J=8.7 Hz, 2H), 7.44 (bs, 2H), 6.79 (d, J=8.4Hz, 1H), 6.28 (d, J=8.1 Hz, 1H), 6.14 (s, 2H), 4.09 (s, 2H). Anal.scalc'd for C₁₈ H₁₂ N₃ S₂ O₄ F₃ : C, 47.47; H, 2.66; N, 9.23. Found: C,47.56; H, 2.73; N, 9.16.

EXAMPLE 34 ##STR371## Step 1. Preparation of3,4-dihydro-α,4-dioxo-7-fluoro-1H-2-benzothiopyran-3-acetic acid, methylester.

7-Fluoroisothiochroman-4-one (Example 31, step 3) (2.0 g, 11 mmol) wasdissolved in anhydrous ethyl ether (50 mL), and sodium methoxide 25% inmethanol (2.6 g, 12 mmol), and dimethyl oxalate (1.42 g, 12 mmol) wereadded. After stirring for 16 hours at room temperature, the mixture waswashed with 1N hydrochloric acid, brine, and water, dried over MgSO₄,concentrated. A brown solid was recrystallized from chloroform/hexanes.(2.5 g, 85%): mp 133°-135° C. ¹ H NMR (DMSO-d₆ 300 MHz) 15.4 (s, 1H),8.03 (dd, J=5.7, 8.7 Hz, 1H), 7.11 (dt, J=2.4, 8.4 Hz, 1H), 6.94(dd,J=2.7, 8.7 Hz, 1H), 3.95(s, 3H), 3.78 (s, 2H). Anal. calc'd. for C₁₂ H₉N₃ SO₄ F: C, 53.73; H, 3.38. Found: C, 53.56; H, 3.42.

Step 2. Preparation of 4- 3-(carbomethoxy)-1,5-dihydro-7-fluoro-2!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

3,4-Dihydro-α,4-dioxo-7-fluoro-1H-2-benzothiopyran-3-acetic acid, methylester from Step 1 (2.5 g, 9 mmol) was dissolved in methanol (100 mL) andp-sulfonamidophenylhydrazine hydrochloride (2.23 g, 10 mmol) was added.The mixture was heated to reflux for 16 hours. After cooling, water wasadded until crystals appeared. The product was collected by filtrationand recrystallized from methanol/water to yield a dark brown solid (3.6g, 95%): mp 241°-244° C. ¹ H NMR (DMSO-d₆ 300 MHz) 7.99 (d, J=8.4 Hz,2H), 7.8 (d, J=8.4 Hz, 2H), 7.56 (s, 2H), 7.42 (dd, J=2.4, 9.0 Hz, 1H),7.08 (dt, J=2.7, 8.7 Hz, 1H), 6.75 (dd, J=5.4, 8.7 Hz, 1H), 4.18 (s,2H), 3.85 (s, 3H). Anal. calc'd. for C₁₈ H₁₄ N₃ O₄ S₂ F₁ : C, 51.54; H,3.36; N, 10.02. Found: C, 51.38; H, 3.44; N, 9.94.

Step 3. Preparation of 4- 3-(carboxamido)-1,5-dihydro-7-fluoro-2!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.

4- 3-(Carbomethoxy)-1,5-dihydro-7-fluoro- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide from Step 2 (1.0 g, 2.4 mmol),methanol (50 mL), and sodium cyanide (0.5 g) were placed in a Parrbottle and pressurized to 20 psig with ammonia gas. After stirring for64 hours at room temperature, the mixture was concentrated, dissolved inethyl acetate, and washed with 1N hydrochloric acid, and water. Thesolution was then dried over MgSO₄ and concentrated. A white solid wasrecrystallized from ethyl acetate/hexanes (0.6 g, 62%): mp 297°-298° C.¹ H NMR (DMSO-d₆ 300 MHz) 7.97 (d, J=8.7 Hz, 2H), 7.78 (d, J=8.7 Hz,2H), 7.74 (bs, 1H), 7.53 (s, 2H), 7.51 (bs, 1H), 7.39 (dd, J=2.7, 9.3Hz, 1H), 7.07 (dt, J=2.7, 9.0 Hz, 1H), 6.75 (dd, J=5.4, 8.7 Hz, 1H), 4.1(s, 2H). Anal. calc'd. for C₁₇ H₁₃ N₄ O₃ S₂ F: C, 50.49; H, 3.24; N,13.85. Found: C, 50.67; H, 3.35; N, 13.60.

Step 4. Preparation of 4-(3-cyano-1,5-dihydro-7-fluoro-2!benzothiopyrano 4,3-c!pyrazol-1-yl) -N-(dimethylamino)methylene!-benzenesulfonamide.

N,N'-Dimethylformamide (3 mL) was cooled with stirring to 0° C. andoxalyl chloride (0.7 g, 5.5 mmol) was added dropwise. 4-3-(Carboxamido)-1,5-dihydro-7-fluoro- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide from Step 3 (1.0 g, 2.5 mmol) wasdissolved in 2 mL of N,N'-dimethylformamide, added dropwise. The mixturewas warmed to room temperature over 0.5 hour when pyridine (2 mL) wasadded followed by ethyl acetate (100 mL). After washing with 1Nhydrochloric acid, brine and water, the mixture was dried over MgSO₄ andconcentrated. A light brown solid was recrystallized from ethylacetate/hexanes (0.8 g, 73%): mp 232°-235° C. ¹ H NMR (DMSO-d₆ 300 MHz)8.26 (s, 1H), 7.95 (d, J=8.7 Hz, 2H), 7.76 (d, J=8.7 Hz, 2H), 7.45 (dd,J=2.7, 9.3 Hz, 1H), 7.13 (dt, J=2.4, 8.4 Hz, 1H), 6.75 (dd, J=5.4, 8.7Hz, 1H), 4.22 (s, 2H), 3.16 (s, 3H), 2.94(s, 3H). Anal. calc'd. for C₂₀H₁₆ N₅ O₂ S₂ F+0.5 H₂ O: C, 53.32; H, 3.80; N, 15.54. Found: C, 53.33;H, 3.78; N, 15.50.

EXAMPLE 35 ##STR372##

4-(1,5-Dihydro-7-fluoro-3-cyano- 2!benzothiopyrano4,3-c!pyrazol-1-yl)-N- (dimethylamino)methylene!benzenesulfonamide(Example 34) (0.7 g, 1.6 mmol) was dissolved in tetrahydrofuran (50 mL)and treated with sodium hydroxide 2.5N (10 mL). After stirring for 5minutes, concentrated hydrochloric acid was added to pH 1. The mixturewas extracted with ethyl acetate (2×30 mL), combined, washed with water,dried over MgSO₄, and concentrated. A tan solid was recrystallized fromethanol/water (0.6 g, 97%): mp 256°-257° C. ¹ H NMR (DMSO-d₆ 300 MHz)8.00 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 7.58 (s, 2H), 7.46 (dd,J=2.7, 9.3 Hz, 1H), 7.11 (dt, J=2.4, 8.4 Hz, 1H), 6.77 (dd, J=5.4, 8.7Hz, 1H), 4.22 (s, 2H). Anal. calc'd. for C₁₇ H₁₁ N₄ O₂ S₂ F: C, 52.84;H, 2.87; N, 14.50. Found: C, 52.69; H, 2.95; N, 14.60.

EXAMPLE 36 ##STR373##

4- 3-(Carbomethoxy)-1,5-dihydro-7-fluoro- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide (Example 34, Step 2)(1.0 g, 2.4mmol) was dissolved in tetrahydrofuran (50 mL) with stirring at roomtemperature. Lithium aluminum hydride 1.0M in tetrahydrofuran (5 mL) wasadded dropwise. After 0.5 hour, 1.25N sodium hydroxide (10 mL) wasadded. The mixture was filtered, concentrated, and purified by flashcolumn chromatography eluting with ethyl acetate:hexanes (2:1). Theappropriate fractions were concentrated and recrystallized from ethylacetate/hexanes. Product was a white solid (0.2 g, 21%): mp 186°-190° C.¹ H NMPR (DMSO-d₆ 300 MHz) 7.92 (d, J=8.7 Hz, 2H), 7.66 (d, J=8.7 Hz,2H), 7.49 (s, 2H), 7.46 (dd, J=2.7, 9.6 Hz, 1H), 7.11 (dt, J=2.7, 8.7Hz, 1H), 6.77 (dd, J=5.7, 8.7 Hz, 1H), 5.72 (t, J=5.7 Hz, 1H), 4.49 (d,J=5.7 Hz, 2H), 4.04 (s, 2H). Anal. calc'd. for C₁₇ H₁₄ N₃ S₂ O₃ F: C,52.16; H, 3.61; N, 10.73. Found: C, 52.42; H, 3.69; N, 10.49.

The following compounds were obtained according to procedures similar tothat exemplified above and in the General Synthetic Schemes.

37) 4- 7-chloro-1,5-dihydro-3-trifluoromethyl-thieno3',2':4,5!thiopyrano-s-oxide 3,2-c!pyrazol-1-yl!benzenesulfonamide:mp=185° C. (dec).

38) 4- 3-(difluoromethyl)-1,5-dihydro-6-fluoro-7-methoxy-2!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide: mp=256°-258° C.

39) 4- 1,5-dihydro-7-fluoro-3-(trifluoromethyl)- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide: mp=240°-242° C.

40) 1-(4-aminosulfonylphenyl)-1,5-dihydro-7-fluoro- 2!benzothiopyrano4,3-c!pyrazol-3-yl!carboxamide: mp=297°-298° C.

41) 4- 1,5-dihydro-6-fluoro-7-methoxy-3-(trifluoromethyl)-2!benzothiopyrano-S-oxide 4,3-c!pyrazol-1-yl!benzenesulfonamide:mp=>300° C.

42) methyl 1-(4-aminosulfonylphenyl)-1,5-dihydro-7-fluoro-2!benzothiopyrano 4,3-c!pyrazol-3-yl!carboxylate: mp=241°-244° C.

43) 4- 4,6-dihydro-7-fluoro-8-methoxy-3-(trifluoromethyl)-2!benzothiepino 5,4-c!pyrazol-1-yl!benzenesulfonamide: mp=133°-138° C.

BIOLOGICAL EVALUATION

Rat Carrageenan Foot Pad Edema Test

The carrageenan foot edema test was performed with materials, reagentsand procedures essentially as described by winter, et al., (Proc. Soc.Exp. Biol. Med., 111, 544 (1962)). Male Sprague-Dawley rats wereselected in each group so that the average body weight was as close aspossible. Rats were fasted with free access to water for over sixteenhours prior to the test. The rats were dosed orally (1 mL) withcompounds suspended in vehicle containing 0.5% methylcellulose and0.025% surfactant, or with vehicle alone. One hour later a subplantarinjection of 0.1 mL of 1% solution of carrageenan/sterile 0.9% salinewas administered and the volume of the injected foot was measured with adisplacement plethysmometer connected to a pressure transducer with adigital indicator. Three hours after the injection of the carrageenan,the volume of the foot was again measured. The average foot swelling ina group of drug-treated animals was compared with that of a group ofplacebo-treated animals and the percentage inhibition of edema wasdetermined (Otterness and Bliven, Laboratory Models for Testing NSAIDS,in Non-steroidal Anti-Inflammatory Drugs, (J. Lombardino, ed. 1985)).The % inhibition shows the % decrease from control paw volume determinedin this procedure and the data for selected compounds in this inventionare summarized in Table XVII.

Rat Carrageenan-induced Analgesia Test

The analgesia test using rat carrageenan was performed with materials,reagents and procedures essentially as described by Hargreaves, et al.,(Pain, 32, 77 (1988)). Male Sprague-Dawley rats were treated aspreviously described for the Carrageenan Foot Pad Edema test. Threehours after the injection of the carrageenan, the rats were placed in aspecial plexiglass container with a transparent floor having a highintensity lamp as a radiant heat source, positionable under the floor.After an initial twenty minute period, thermal stimulation was begun oneither the injected foot or on the contralateral uninjected foot. Aphotoelectric cell turned off the lamp and timer when light wasinterrupted by paw withdrawal. The time until the rat withdraws its footwas then measured. The withdrawal latency in seconds was determined forthe control and drug-treated groups, and percent inhibition of thehyperalgesic foot withdrawal determined. Results are shown in TableXVII.

                  TABLE XVII    ______________________________________                RAT PAW EDEMA                             ANALGESIA    Example     % Inhibition.sup.1                             % Inhibition.sup.1    ______________________________________    1           43           35    2           28           29    21          26           14    ______________________________________     .sup.1@ 30 mg/kg body weight

Evaluation of COX-1 and COX-2 activity in vitro

The compounds of this invention exhibited inhibition in vitro of COX-2.The COX-2 inhibition activity of the compounds of this inventionillustrated in the Examples was determined by the following methods.

a. Preparation of recombinant COX baculoviruses

A 2.0 kb fragment containing the coding region of either human or murineCOX-1 or human or murine COX-2 was cloned into a BamH1 site of thebaculovirus transfer vector pVL1393 (Invitrogen) to generate thebaculovirus transfer vectors for COX-1 and COx-2 in a manner similar tothe method of D. R. O'Reilly et al (Baculovirus Expression Vectors: ALaboratory Manual (1992)). Recombinant baculoviruses were isolated bytransfecting 4 μg of baculovirus transfer vector DNA into SF9 insectcells (2>10e8) along with 200 ng of linearized baculovirus plasmid DNAby the calcium phosphate method. See M. D. Summers and G. E. Smith, AManual of Methods for Baculovirus Vectors and Insect Cell CultureProcedures, Texas Agric. Exp. Station Bull. 1555 (1987). Recombinantviruses were purified by three rounds of plaque purification and hightiter (10E7-10E8 pfu/ml) stocks of virus were prepared. For large scaleproduction, SF9 insect cells were infected in 10 liter fermentors(0.5×10⁶ /ml) with the recombinant baculovirus stock such that themultiplicity of infection was 0.1. After 72 hours the cells werecentrifuged and the cell pellet homogenized in Tris/Sucrose (50 mM: 25%,pH 8.0) containing 1% 3-(3-cholamidopropyl)dimethylammoniol!-1-propanesulfonate (CHAPS). Thehomogenate was centrifuged at 10,000×G for 30 minutes, and the resultantsupernatant was stored at -80° C. before being assayed for Cox activity.

b. Assay for COX-1 and COX-2 activity:

COX activity was assayed as PGE₂ formed/μg protein/time using an ELISAto detect the prostaglandin released. CHAPS-solubilized insect cellmembranes containing the appropriate COX enzyme were incubated in apotassium phosphate buffer (50 mM, pH 8.0) containing epinephrine,phenol, and heme with the addition of arachidonic acid (10 μM).Compounds were pre-incubated with the enzyme for 10-20 minutes prior tothe addition of arachidonic acid. Any reaction between the arachidonicacid and the enzyme was stopped after ten minutes at 37° C./roomtemperature by transferring 40 μl of reaction mix into 160 μl ELISAbuffer and 25 μM indomethacin. The PGE₂ formed was measured by standardELISA technology (Cayman Chemical). Results are shown in Table XVIII.

                  TABLE XVIII    ______________________________________                 Human COX-2                            Human COX-1    Example      IC.sub.50  μM                            IC.sub.50  μM    ______________________________________    1            <0.1       2.7    2            <0.1       >100    3            1.3        7.1    4            0.5    5            4.8        24.4    6            23.5       11.1    7            0.5        9.7    8            0.5    9            48.2       >100    10           <0.1       6.2    11           52         >100    12           95         >100    13           <0.1       <0.1    14           0.2        4.6    15           <0.1       0.3    16           <0.1       0.4    17           <0.1       0.8    18           <0.1       3.7    19           <0.1       0.3    20           <0.1       <0.1    21           <0.1       8.7    22           3.5        51    24           <0.1       1.2    25           <0.1       1.5    26           <0.1       0.2    27           59.9       >100    28           <0.1       >100    29           0.3        >100    30           <0.1       10.7    31           <0.1       0.2    32           0.2        8.9    33           <0.1       <0.1    34           4.2        >100    35           0.1        0.8    36           1.7        6.7    37           45.6       91.1    38           <0.1       >100    39           <0.1       0.3    40           4.7        >100    41           1.2        >100    42           0.8        13.2    43           2.2        73.4    ______________________________________

Biological paradigms for testing the cytokine-inhibiting activity ofthese compounds are found in WO995/13067, published 18 May 1995.

Also embraced within this invention is a class of pharmaceuticalcompositions comprising the active compounds of this combination therapyin association with one or more non-toxic, pharmaceutically-acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as "carrier" materials) and, if desired, other activeingredients. The active compounds of the present invention may beadministered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The active compounds andcomposition may, for example, be administered orally, intravascularly,intraperitoneally, subcutaneously, intramuscularly or topically.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. The active ingredient mayalso be administered by injection as a composition wherein, for example,saline, dextrose or water may be used as a suitable carrier.

The amount of therapeutically active compounds that are administered andthe dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention depends on a variety of factors,including the age, weight, sex and medical condition of the subject, theseverity of the disease, the route and frequency of administration, andthe particular compound employed, and thus may vary widely. Thepharmaceutical compositions may contain active ingredients in the rangeof about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mgand most preferably between about 1 and 100 mg. A daily dose of about0.01 to 100 mg/kg body weight, preferably between about 0.5 and about 20mg/kg body weight and most preferably between about 0.1 to 10 mg/kg bodyweight, may be appropriate. The daily dose can be administered in one tofour doses per day.

In the case of psoriasis and other skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day.

For inflammations of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream, or as a suppository, containing the active ingredients in a totalamount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w andmost preferably 0.4 to 15% w/w. When formulated in an ointment, theactive ingredients may be employed with either paraffinic or awater-miscible ointment base. Alternatively, the active ingredients maybe formulated in a cream with an oil-in-water cream base. If desired,the aqueous phase of the cream base may include, for example at least30% w/w of a polyhydric alcohol such as propylene glycol,butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol andmixtures thereof. The topical formulation may desirably include acompound which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include dimethylsulfoxide and relatedanalogs. The compounds of this invention can also be administered by atransdermal device. Preferably topical administration will beaccomplished using a patch either of the reservoir and porous membranetype or of a solid matrix variety. In either case, the active agent isdelivered continuously from the reservoir or microcapsules through amembrane into the active agent permeable adhesive, which is in contactwith the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. The antiinflammatory active ingredients are preferablypresent in such formulations in a concentration of 0.5 to 20%,advantageously 0.5 to 10% and particularly about 1.5% w/w.

For therapeutic purposes, the active compounds of this combinationinvention are ordinarily combined with one or more adjuvants appropriateto the indicated route of administration. If administered per os, thecompounds may be admixed with lactose, sucrose, starch powder, celluloseesters of alkanoic acids, cellulose alkyl esters, talc, stearic acid,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor nonaqueous isotonic sterile injection solutions or suspensions. Thesesolutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations.

What is claimed is:
 1. A compound selected from compounds, and theirpharmaceutically acceptable salts, of the group consisting of4-3-(difluoromethyl)-1,5-dihydro-7-methyl- 2!benzopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide; 4-1,5-dihydro-7,8,9-trimethoxy-3-(trifluoromethyl)- 2!benzopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide; 4-7-chloro-3-(difluoromethyl)-1,5-dihydro- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide; 4-1,5-dihydro-3-(trifluoromethyl)- 1,3!dioxolo 6,7! 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide; 4-7-fluoro-1,5-dihydro-3-(hydroxymethyl)- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide; 4-3-(difluoromethyl)-1,5-dihydro-7-methyl- 2!benzenethiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide; 4- 3-cyano-7-fluoro-1,5-dihydro-2!benzothiopyrano 4,3-c!pyrazol-1-yl!-N-(dimethylamino)methylene!benzenesulfonamide; 4-3-(difluoromethyl)-7-fluoro-1,5-dihydro- 2!benzothiopyrano4,3-c!pyrazol-1-yl!benzenesulfonamide; 4- 3-cyano-7-fluoro-1,5-dihydro-2!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide; and 4-6,8-difluoro-1,5-dihydro-7-methoxy-3-(trifluoromethyl)-2!benzothiopyrano 4,3-c!pyrazol-1-yl!benzenesulfonamide.
 2. Apharmaceutical composition comprising a therapeutically-effective amountof a compound, said compound selected from a family of compounds ofclaim 1, or a pharmaceutically-acceptable salt thereof.
 3. A method oftreating inflammation or an inflammation-associated disorder in asubject, said method comprising administering to the subject having orsusceptible to said inflammation or inflammation-associated disorder, atherapeutically-effective amount of a compound of claim 1, or apharmaceutically-acceptable salt thereof.
 4. The method of claim 3 foruse in treatment of inflammation.
 5. The method of claim 3 for use intreatment of an inflammation-associated disorder.
 6. The method of claim5 wherein the inflammation-associated disorder is arthritis.
 7. Themethod of claim 5 wherein the inflammation-associated disorder is pain.8. The method of claim 5 wherein the inflammation-associated disorder isfever.